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Background: Relapse and refractory (R/R) rates after first‐line R‐CHOP in diffuse large B cell lymphomas (DLBCL) are ~40% and ~15% respectively. Aims: We conducted a retrospective real‐world analysis aimed at evaluating clinical outcomes of R/R DLBCL patients. Material and Methods: Overall, 403 consecutive DLBCL patients treated in two large hematological centers in Torino, Italy were reviewed. Results: At a median follow up of 50 months, 5‐year overall survival from diagnosis (OS‐1) was 66.5%, and 2‐year progression free survival (PFS‐1) was 68%. 134 (34.4%) patients relapsed (n = 46, 11.8%) or were refractory (n = 88, 22.6%) to R‐CHOP. Most employed salvage treatments included platinum salt‐based regimens in 38/134 (28.4%), lenalidomide in 14 (10.4%). Median OS and PFS after disease relapse or progression (OS‐2 and PFS‐2) were 6.7 and 5.1 months respectively. No significant difference in overall response rate, OS‐2 or PFS‐2 in patients treated with platinum‐based regimens versus other regimens was observed. By multivariate analysis, age between 60 and 80 years, germinal center B cell type cell of origin and extranodal involvement of <2 sites were associated with better OS‐2. Discussion: Our findings confirm very poor outcomes of R/R DLBCL in the rituximab era. Widespread approval by national Medicine Agencies of novel treatments such as CAR‐T cells and bispecific antibodies as second‐line is eagerly awaited to improve these outcomes. [ABSTRACT FROM AUTHOR]

Broadly neutralizing antibodies are proposed as therapeutic and prophylactic agents against HIV‐1, but their potency and breadth are less than optimal. This study describes the immunization of a llama with the prefusion‐stabilized HIV‐1 envelope (Env) trimer, BG505 DS‐SOSIP, and the identification and improvement of potent neutralizing nanobodies recognizing the CD4‐binding site (CD4bs) of vulnerability. Two of the vaccine‐elicited CD4bs‐targeting nanobodies, G36 and R27, when engineered into a triple tandem format with llama IgG2a‐hinge region and human IgG1‐constant region (G36×3‐IgG2a and R27×3‐IgG2a), neutralized 96% of a multiclade 208‐strain panel at geometric mean IC80s of 0.314 and 0.033 µg mL−1, respectively. Cryo‐EM structures of these nanobodies in complex with Env trimer revealed the two nanobodies to neutralize HIV‐1 by mimicking the recognition of the CD4 receptor. To enhance their neutralizing potency and breadth, nanobodies are linked to the light chain of the V2‐apex‐targeting broadly neutralizing antibody, CAP256V2LS. The resultant human‐llama bispecific antibody CAP256L‐R27×3LS exhibited ultrapotent neutralization and breadth exceeding other published HIV‐1 broadly neutralizing antibodies, with pharmacokinetics determined in FcRn‐Fc mice similar to the parent CAP256V2LS. Vaccine‐elicited llama nanobodies, when combined with V2‐apex broadly neutralizing antibodies, may therefore be able to fulfill anti‐HIV‐1 therapeutic and prophylactic clinical goals. [ABSTRACT FROM AUTHOR]

This article discusses the potential synergistic effect of combining FOXM1 and BCL-2 inhibitors in the treatment of multiple myeloma (MM). The study conducted in vivo and ex vivo experiments to confirm the effectiveness of this combination therapy. The results showed that the combination of a FOXM1 inhibitor (NB73) and a BCL-2 inhibitor (venetoclax) significantly extended the survival of mice with MM compared to control groups. The study also developed a simplified ex vivo culture protocol for testing primary MM cells, which could be implemented in community hospitals. However, the study acknowledges its limitations and calls for further research to explore the underlying mechanisms of the synergistic effect. [Extracted from the article]

Light chain (AL) amyloidosis is a plasma cell disorder distinguished from multiple myeloma (MM) by the degree of organ involvement due to tissue deposition of misfolded proteins. Treatments for AL amyloidosis have largely been borrowed from those developed for patients with MM. High-dose chemotherapy followed by autologous stem cell transplant (ASCT) has historically been associated with the best outcomes. The recent incorporation of daratumumab into up front therapy represents a significant advance and has changed the treatment paradigm, calling into question the role of ASCT. The development of very active novel immune and cellular therapies, specifically B cell maturation antigen (BCMA)-directed therapies, has similarly been transformative for patients with MM and is now being studied in patients with AL amyloidosis. These include chimeric antigen receptor (CAR) T cells, bispecific antibodies, and antibody drug conjugates. Although limited, preliminary data in patients with relapsed and refractory AL amyloidosis are showing promising results, and it is expected that the treatment landscape for AL amyloidosis will continue to evolve. Particular attention to safety, potential for organ recovery, and quality of life will be important when evaluating new treatments and/or treatment paradigms. [ABSTRACT FROM AUTHOR]

Background: CD38 and CD47 are expressed in many hematologic malignancies, including multiple myeloma (MM), B-cell non-Hodgkin lymphoma (NHL), B-cell acute lymphoblastic leukemia (ALL), and B-cell chronic lymphocytic leukemia (CLL). Here, we evaluated the antitumor activities of CD38/CD47 bispecific antibodies (BsAbs). Methods: Five suitable anti-CD38 antibodies for co-targeting CD47 and CD38 BsAb were developed using a 2 + 2 "mAb-trap" platform. The activity characteristics of the CD38/CD47 BsAbs were evaluated using in vitro and in vivo systems. Results: Using hybridoma screening technology, we obtained nine suitable anti-CD38 antibodies. All anti-CD38 antibodies bind to CD38+ tumor cells and kill tumor cells via antibody-dependent cellular cytotoxicity (ADCC) and antibodydependent cellular phagocytosis (ADCP). Five anti-CD38 antibodies (4A8, 12C10, 26B4, 35G5, and 65A7) were selected for designing CD38/CD47 BsAbs (IMM5605) using a "mAb-trap" platform. BsAbs had higher affinity and binding activity to the CD38 target than those to the CD47 target, decreasing the potential on-target potential and off-tumor effects. The CD38/CD47 BsAbs did not bind to RBCs and did not induce RBC agglutination; thus, BsAbs had much lower blood toxicity. The CD38/CD47 BsAbs had a greater ability to block the CD47/SIRPa signal in CD38+/CD47+ tumor cells than IMM01 (SIRPa Fc fusion protein). Through Fc domain engineering, CD38/CD47 BsAbs were shown to kill tumors more effectively by inducing ADCC and ADCP. IMM5605-26B4 had the strongest inhibitory effect on cellular CD38 enzymatic activity. IMM5605-12C10 had the strongest ability to directly induce the apoptosis of tumor cells. The anti- CD38 antibody 26B4 combined with the SIRPa-Fc fusion proteins showed strong antitumor effects, which were better than any of the mono-therapeutic agents used alone in the NCI-H929 cell xenograft model. The CD38/CD47 BsAbs exhibited strong antitumor effects; specifically, IMM5605-12C10 efficiently eradicated all established tumors in all mice.Conclusion: A panel of BsAbs targeting CD38 and CD47 developed based on the "mAb-tarp" platform showed potent tumor-killing ability in vitro and in vivo. As BsAbs had lower affinity for binding to CD47, higher affinity for binding to CD38, no affinity for binding to RBCs, and did not induce RBC agglutination, we concluded that CD38/CD47 BsAbs are safe and have a satisfactory tolerability profile. [ABSTRACT FROM AUTHOR]

So-called innovative immunotherapies targeting mainly the BCMA antigen have rapidly become established in the relapse setting for patients with multiple myeloma (MM). Elranatamab and téclistamab, two bispecific antibodies that bring T lymphocytes closer to the tumor cell, are currently available for early access in France as fourth-line treatments. Today, these molecules are prescribed with great efficacy as monotherapy, which has become unprecedented in myeloma, but their place in the therapeutic strategy remains to be better defined. Ongoing trials are proposing combinations between two bispecifics or with more conventional treatments for MM, as well as trials in first-line treatment, whether in induction or after intensification (during maintenance, for example). The main side effects are the risk of cytokine release syndrome (CRS) and ICANS, which are uncommon, but also an increased risk of infection, which has led to specific recommendations. [ABSTRACT FROM AUTHOR]

One of the well-known X-linked genetic disorders is hemophilia, which could be hemophilia A as a result of a mutation in the F8 (factor VIII) gene or hemophilia B as a result of a mutation in the F9 (factor IX) gene, leading to insufficient levels of the proteins essential for blood coagulation cascade. In patients with severe hemophilia, factor VIII or factor IX activities in the blood plasma are considerably low, estimated to be less than 1%. This is responsible for spontaneous or post-traumatic bleeding episodes, or both, leading to disease complications and death. Current treatment of hemophilia relies on the prevention of bleeding, which consists of expensive lifelong replacement infusion therapy of blood plasma clotting factors, their recombinant versions, or therapy with recombinant monoclonal antibodies. Recently emerged gene therapy approaches may be a potential game changer that could reshape the therapeutic outcomes of hemophilia A or B using a one-off vector in vivo delivery and aim to achieve long-term endogenous expression of factor VIII or IX. This review examines both traditional approaches to the treatment of hemophilia and modern methods, primarily focusing on gene therapy, to update knowledge in this area. Recent technological advances and gene therapeutics in the pipeline are critically reviewed and summarized. We consider gene therapy to be the most promising method as it may overcome the problems associated with more traditional treatments, such as the need for constant and expensive infusions and the presence of an immune response to the antibody drugs used to treat hemophilia. [ABSTRACT FROM AUTHOR]

Summary: We reviewed cases with aggressive B‐cell non‐Hodgkin lymphoma who relapsed or progressed following glofitamab. The prognosis was poor, with low rates of response to subsequent salvage therapies, and a median overall survival of 4.1 months from the time of progression. There were high rates of CD20 loss (59%) at the time of relapse. In a field where CD20 × CD3 bispecific antibodies are entering routine clinical use, our experience highlights a potential means of resistance. It illustrates both the need to further characterise mechanisms of CD20 loss, and to pursue clinical trials of novel non‐CD20‐directed treatments in this cohort. [ABSTRACT FROM AUTHOR]

The advent of targeted therapies such as monoclonal antibodies, adoptive T-cell therapies, and antibody–drug conjugates (ADCs) dramatically changed the treatment landscape of diffuse large B-cell lymphoma (DLBCL) over the last two decades. Rituximab was the first one approved. Chimeric antigen receptor T-cells are currently approved as second-line treatment in patients with DLBCL refractory to first-line chemo-immunotherapy. Polatuzumab, a CD79b-targeting ADC, is approved as first-line treatment in high-risk patients in combination with chemo-immunotherapy. Bispecific antibodies (BsAbs) are a novel category of drugs that are also changing the treatment paradigm of patients with DLBCL. They are engineered to bind to two different targets at the same time. To date, two BsAbs (glofitamab and epcoritamab) are approved as monotherapy in third-line treatment in DLBCL. Combination strategies with chemotherapy, immunotherapy, and ADCs are currently under investigation with encouraging results in first-line or subsequent lines of treatment. In the following review, we focus on the structure of BsAbs, the mechanism of action, clinical efficacy, and the mechanisms of resistance to BsAbs. [ABSTRACT FROM AUTHOR]

Current therapies targeting the human epidermal growth factor receptor (HER) family, including monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), are limited by drug resistance and systemic toxicities. Antibody–drug conjugates (ADCs) are one of the most rapidly expanding classes of anti-cancer therapeutics with 13 presently approved by the FDA. Importantly, ADCs represent a promising therapeutic option with the potential to overcome traditional HER-targeted therapy resistance by delivering highly potent cytotoxins specifically to HER-overexpressing cancer cells and exerting both mAb- and payload-mediated antitumor efficacy. The clinical utility of HER-targeted ADCs is exemplified by the immense success of HER2-targeted ADCs including trastuzumab emtansine and trastuzumab deruxtecan. Still, strategies to improve upon existing HER2-targeted ADCs as well as the development of ADCs against other HER family members, particularly EGFR and HER3, are of great interest. To date, no HER4-targeting ADCs have been reported. In this review, we extensively detail clinical-stage EGFR-, HER2-, and HER3-targeting monospecific ADCs as well as novel clinical and pre-clinical bispecific ADCs (bsADCs) directed against this receptor family. We close by discussing nascent trends in the development of HER-targeting ADCs, including novel ADC payloads and HER ligand-targeted ADCs. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite significant advancements, acute myeloid leukemia (AML) still remains characterized by a dismal prognosis in too many patients, and oftentimes, a cure can be achieved only after allogeneic hematopoietic stem cell transplantation (allo-HSCT), a procedure hampered by severe treatment-related complications. Despite this, new technologies have made it possible to harness the activity of the immune system against AML and use it as a new form of therapy, and intense research in the field has been made in recent years. This review aims to summarize the main concepts and strategies under study, considered from the point of view of the practicing hematologist, with special interest in the underlying biological principles and on treatment safety and efficacy. It will hopefully provide physicians, as well as the curious enthusiasts, with an updated, critically assessed description of immunotherapy as part of a more precise oncology approach to the treatment of AML. The potential of the immune system to eradicate leukemic cells has been consistently demonstrated by the Graft vs. Leukemia effect occurring after allo-HSCT and in the context of donor leukocyte infusions. Various immunotherapeutic approaches, ranging from the use of antibodies, antibody–drug conjugates, bispecific T-cell engagers, chimeric antigen receptor (CAR) T-cells, and therapeutic infusions of NK cells, are thus currently being tested with promising, yet conflicting, results. This review will concentrate on various types of immunotherapies in preclinical and clinical development, from the point of view of a clinical hematologist. The most promising therapies for clinical translation are the use of bispecific T-cell engagers and CAR-T cells aimed at lineage-restricted antigens, where overall responses (ORR) ranging from 20 to 40% can be achieved in a small series of heavily pretreated patients affected by refractory or relapsing leukemia. Toxicity consists mainly in the occurrence of cytokine-release syndrome, which is mostly manageable with step-up dosing, the early use of cytokine-blocking agents and corticosteroids, and myelosuppression. Various cytokine-enhanced natural killer products are also being tested, mainly as allogeneic off-the-shelf therapies, with a good tolerability profile and promising results (ORR: 20–37.5% in small trials). The in vivo activation of T lymphocytes and NK cells via the inhibition of their immune checkpoints also yielded interesting, yet limited, results (ORR: 33–59%) but with an increased risk of severe Graft vs. Host disease in transplanted patients. Therefore, there are still several hurdles to overcome before the widespread clinical use of these novel compounds. [ABSTRACT FROM AUTHOR]

Simple Summary: Bispecific antibodies (BsAbs) provide a new mode of targeting multiple myeloma (MM) plasma cells (PCs), basing their action on the activation and redirection of the T-cell compartment against neoplastic cells. Two BCMA-targeting (teclistamab and elranatamab) plus one GPRC5D-targeting (talquetamab) BsAbs are available for the management of heavily pretreated patients with relapsed/refractory (RR) MM. Novel strategies to augment potency, reduce toxicity, and improve management are under investigation. This review summarizes the clinical applications of BsAbs and discusses the current challenges of the treatment and opportunities for optimization. Bispecific antibodies (BsAbs) are artificially engineered antibodies that can bind simultaneously to the CD3 subunit within the T-cell receptor complex and an antigen on tumor cells, leading to T-cell activation and tumor cell killing. BsAbs against BCMA or GPRC5D have shown impressive clinical activity in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), with some agents having already received regulatory approval after the third (by the European Medicines Agency, EMA) or fourth (by the Food and Drug Administration, FDA) line of therapy; the results of early-phase clinical trials targeting FcRH5 are also promising. Overall, BsAbs as monotherapy correlated with an ORR that exceeded 60%, with a high CR rate ranging between 25% and 50% and a median PFS of around 1 year among patients with a median of 4–6 prior lines of therapy. The main toxicities include cytokine release syndrome, cytopenias, hypogammaglobulinemia, and infections; on-target off-tumor adverse events involving the skin, mucosa, hair, and nails may also occur with anti-GPRC5D BsAbs. Active research to increase their efficacy and improve their tolerance is still in progress, including combination therapies and application in earlier treatment lines and the development of novel agents. A better understanding of the mechanisms of resistance is a challenge and could lead to more personalized approaches. [ABSTRACT FROM AUTHOR]

Antibody-based therapies are revolutionizing cancer treatment and experience a steady increase from preclinical and clinical pipelines to market share. While the clinical success of monoclonal antibodies is frequently limited by low response rates, treatment resistance and various other factors, multispecific antibodies open up new prospects by addressing tumor complexity as well as immune response actuation potently improving safety and efficacy. Novel antibody approaches involve simultaneous binding of two antigens on one cell implying increased specificity and reduced tumor escape for dual tumor-associated antigen targeting and enhanced and durable cytotoxic effects for dual immune cell-related antigen targeting. This article reviews antibody and cell-based therapeutics for oncology with intrinsic dual targeting of either tumor cells or immune cells. As revealed in various preclinical studies and clinical trials, dual targeting molecules are promising candidates constituting the next generation of antibody drugs for fighting cancer. [ABSTRACT FROM AUTHOR]

The management of hemophilia A has undergone a remarkable revolution, in line with technological advancement. In the recent past, the primary concern associated with Factor VIII (FVIII) concentrates was the risk of infections, which is now almost resolved by advanced blood screening and viral inactivation methods. Improving patients' compliance with prophylaxis has become a key focus, as it can lead to improved health outcomes and reduced health care costs in the long term. Recent bioengineering research is directed toward prolonging the recombinant FVIII (rFVIII) coagulant activity and synthesising higher FVIII yields. As an outcome, B-domain deleted, polyethylene glycolated, single-chain, Fc-fused rFVIII, and rFVIIIFc-von Willebrand Factor-XTEN are available for patients. Moreover, emicizumab, a bispecific antibody, is commercially available, whereas fitusiran and tissue factor pathway inhibitor are in clinical trial stages as alternative strategies for patients with inhibitors. With these advancements, noninfectious complications, such as inhibitor development, allergic reactions, and thrombosis, are emerging concerns requiring careful management. In addition, the recent approval of gene therapy is a major milestone toward a permanent cure for hemophilia A. The vast array of treatment options at our disposal today empowers patients and providers alike, to tailor therapeutic regimens to the unique needs of each individual. Despite significant progress in modern treatment options, these highly effective therapies are markedly more expensive than conventional replacement therapy, limiting their access for patients in developing countries. [ABSTRACT FROM AUTHOR]

Recently, bispecific antibodies (BsAbs) are evolving the landscape of cancer treatment and have significantly improved the outcomes of relapsed or refractory cancer patients. As increasing BsAbs entered clinical practice, specific toxicities have emerged, and renal side-effects have been described. However, there are a lack of studies analyzing the nephrotoxicity in the anti-cancer BsAbs recipients systematically. In this review, we demonstrate the etiologies, mechanisms, other risk factors and treatment options of kidney injury in the BsAbs recipients to provide a more comprehensive insight into the nephrotoxicity post-BsAbs therapy. Significantly, due to the limited clinical trial data on each subject, we mainly conclude the related etiologies, mechanisms, and risk factors of nephrotoxicity that occur in T-cell-engaging BsAbs recipients. Nephrotoxicity associated with non-T-cell BsAbs may be associated with adverse nephrotoxicity of related monoclonal antibodies to two specific antigens. The aim of this paper is to provide nephrologists and oncologists with theoretical knowledge to provide better medical management for recipients who receive BsAbs, especially T-cell-engaging BsAbs treatment. [ABSTRACT FROM AUTHOR]

This article explores the use of Physiologically Based Pharmacokinetic (PBPK) modeling to assess drug interactions caused by cytokine release syndrome (CRS) in regulatory submissions for bispecific antibodies. It discusses the current practices and positions of the FDA and sponsors regarding PBPK modeling in evaluating CRS-mediated drug interactions. The authors highlight the gaps between peer-reviewed papers and regulatory evaluations in determining the impact of PBPK predictions. They advocate for improved predictive performance and a patient-centric clinical pharmacology approach to better understand and manage CRS-mediated drug interactions. Additionally, the article discusses the current practice of informing healthcare providers and patients about drug interactions related to CRS and proposes the use of PBPK modeling to enhance the clinical use of concomitant medications during CRS events. The authors identify gaps in current PBPK modeling and suggest approaches to address these gaps and improve the predictability of PBPK. Their goal is to use a quantitative approach to better inform patients and healthcare providers about the risks of CRS-mediated drug interactions. [Extracted from the article]

Multiple myeloma (MM) is the second most common hematological malignancy of plasma cells, characterized by osteolytic bone lesions, anemia, hypercalcemia, renal failure, and the accumulation of malignant plasma cells. The pathogenesis of MM involves the interaction between MM cells and the bone marrow microenvironment through soluble cytokines and cell adhesion molecules, which activate various signaling pathways such as PI3K/AKT/mTOR, RAS/MAPK, JAK/STAT, Wnt/β-catenin, and NF-κB pathways. Aberrant activation of these pathways contributes to the proliferation, survival, migration, and drug resistance of myeloma cells, making them attractive targets for therapeutic intervention. Currently, approved drugs targeting these signaling pathways in MM are limited, with many inhibitors and inducers still in preclinical or clinical research stages. Therapeutic options for MM include non-targeted drugs like alkylating agents, corticosteroids, immunomodulatory drugs, proteasome inhibitors, and histone deacetylase inhibitors. Additionally, targeted drugs such as monoclonal antibodies, chimeric antigen receptor T cells, bispecific T-cell engagers, and bispecific antibodies are being used in MM treatment. Despite significant advancements in MM treatment, the disease remains incurable, emphasizing the need for the development of novel or combined targeted therapies based on emerging theoretical knowledge, technologies, and platforms. In this review, we highlight the key role of signaling pathways in the malignant progression and treatment of MM, exploring advances in targeted therapy and potential treatments to offer further insights for improving MM management and outcomes. [ABSTRACT FROM AUTHOR]

The human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase receptor and tumor-associated antigen abnormally expressed in various types of cancer, including breast, ovarian, and gastric cancer. HER2 overexpression is highly correlated with increased tumor aggressiveness, poorer prognosis, and shorter overall survival. Consequently, multiple HER2-targeted therapies have been developed and approved; however, only a subset of patients benefit from these treatments, and relapses are common. More potent and durable HER2-targeted therapies are desperately needed for patients with HER2-positive cancers. In this study, we developed a lipid nanoparticle (LNP)-based therapy formulated with mRNA encoding a novel HER2-CD3-Fc bispecific antibody (bsAb) for HER2-positive cancers. The LNPs efficiently transfected various types of cells, such as HEK293S, SKOV-3, and A1847, leading to robust and sustained secretion of the HER2-CD3-Fc bsAb with high binding affinity to both HER2 and CD3. The bsAb induced potent T-cell-directed cytotoxicity, along with secretion of IFN-λ, TNF-α, and granzyme B, against various types of HER2-positive tumor cells in vitro, including A549, NCI-H460, SKOV-3, A1847, SKBR3, and MDA-MB-231. The bsAb-mediated antitumor effect is highly specific and strictly dependent on its binding to HER2, as evidenced by the gained resistance of A549 and A1847 her2 knockout cells and the acquired sensitivity of mouse 4T1 cells overexpressing the human HER2 extracellular domain (ECD) or epitope-containing subdomain IV to the bsAb-induced T cell cytotoxicity. The bsAb also relies on its binding to CD3 for T-cell recruitment, as ablation of CD3 binding abolished the bsAb's ability to elicit antitumor activity. Importantly, intratumoral injection of the HER2-CD3-Fc mRNA-LNPs triggers a strong antitumor response and completely blocks HER2-positive tumor growth in a mouse xenograft model of human ovarian cancer. These results indicate that the novel HER2-CD3-Fc mRNA-LNP-based therapy has the potential to effectively treat HER2-positive cancer. [ABSTRACT FROM AUTHOR]

Rationale:Pseudomonas aeruginosa infection is associated with worse outcomes in bronchiectasis. Impaired neutrophil antimicrobial responses contribute to bacterial persistence. Gremubamab is a bivalent, bispecific monoclonal antibody targeting Psl exopolysaccharide and the type 3 secretion system component PcrV. Objectives: This study evaluated the efficacy of gremubamab to enhance killing of P. aeruginosa by neutrophils from patients with bronchiectasis and to prevent P. aeruginosa–associated cytotoxicity. Methods:P. aeruginosa isolates from a global bronchiectasis cohort (n = 100) underwent whole-genome sequencing to determine target prevalence. Functional activity of gremubamab against selected isolates was tested in vitro and in vivo. Patients with bronchiectasis (n = 11) and control subjects (n = 10) were enrolled, and the effect of gremubamab in peripheral blood neutrophil opsonophagocytic killing (OPK) assays against P. aeruginosa was evaluated. Serum antibody titers to Psl and PcrV were determined (n = 30; 19 chronic P. aeruginosa infection, 11 no known P. aeruginosa infection), as was the effect of gremubamab treatment in OPK and anti–cytotoxic activity assays. Measurements and Main Results: Psl and PcrV were conserved in isolates from chronically infected patients with bronchiectasis. Seventy-three of 100 isolates had a full psl locus, and 99 of 100 contained the pcrV gene, with 20 distinct full-length PcrV protein subtypes identified. PcrV subtypes were successfully bound by gremubamab and the monoclonal antibody–mediated potent protective activity against tested isolates. Gremubamab increased bronchiectasis patient neutrophil-mediated OPK (+34.6 ± 8.1%) and phagocytosis (+70.0 ± 48.8%), similar to effects observed in neutrophils from control subjects (OPK, +30.1 ± 7.6%). No evidence of competition between gremubamab and endogenous antibodies was found, with protection against P. aeruginosa–induced cytotoxicity and enhanced OPK demonstrated with and without addition of patient serum. Conclusions: Gremubamab enhanced bronchiectasis patient neutrophil phagocytosis and killing of P. aeruginosa and reduced virulence. [ABSTRACT FROM AUTHOR]

Modern immunochemotherapy protocols allow 60-70% of diffuse large B-cell lymphoma (DLBCL) patients to be cured by first-line therapy. Those with primary resistance or early relapse have a poor prognosis, and classical salvage regimens are effective in less than 20% of these patients. Targeted chemotherapy and immunotherapy protocols are considered the current standard of care. Chimeric antigen receptor T cell (CAR-T cell) therapy and bispecific antibodies (BsAbs) are regarded as the two most effective methods. Epcoritamab and glofitamab are novel BsAbs approved for the treatment of DLBCL after two lines of systemic therapy. Their high efficacy and safety have been confirmed in phase II multicenter studies. BsAbs are an alternative to CAR-T cell therapy in patients who do not qualify for it or who cannot wait for CAR-T cell preparation due to rapidly progressing disease. Although BsAbs are approved as monotherapy, combinations with chemotherapy and immunomodulatory agents are being explored in ongoing clinical studies. The high efficacy of BsAbs has prompted further research into their potential role in earlier lines of treatment, including first line and debulking before CAR-T cell therapies. [ABSTRACT FROM AUTHOR]

Introduction: Bispecific antibodies (BsAbs) can simultaneously target two epitopes of different antigenic targets, bringing possibilities for diversity in antibody drug design and are promising tools for the treatment of cancers and other diseases. T-cell engaging bsAb is an important application of the bispecific antibody, which could promote T cell-mediated tumor cell killing by targeting tumor-associated antigen (TAA) and CD3 at the same time. Methods: This study comprised antibodies purification, Elisa assay for antigen binding, cytotoxicity assays, T cell activation by flow cytometry in vitro and xenogenic tumor model in vivo. Results: We present a novel bsAb platform named PHE-Ig technique to promote cognate heavy chain (HC)-light chain (LC) pairing by replacing the CH1/CL regions of different monoclonal antibodies (mAbs) with the natural A and B chains of PHE1 fragment of Integrin b2 based on the knob-in-hole (KIH) technology. We had also verified that PHE-Ig technology can be effectively used as a platform to synthesize different desired bsAbs for T-cell immunotherapy. Especially, BCMA×CD3 PHE-Ig bsAbs exhibited robust antimultiple myeloma (MM) activity in vitro and in vivo. Discussion: Moreover, PHE1 domain was further shortened with D14G and R41S mutations, named PHE-S, and the PHE-S-based BCMA×CD3 bsAbs also showed anti BCMA+ tumor effect in vitro and in vivo, bringing more possibilities for the development and optimization of different bsAbs. To sum up, PHE1-based IgGlike antibody platform for bsAb construction provides a novel strategy for enhanced T-cell immunotherapy. [ABSTRACT FROM AUTHOR]

Ichnos has developed a multi-specific antibody platform based on the BEAT® (Bispecific engagement by antibodies based on the T-cell receptor) interface. The increased complexity of the bi- and multi-specific formats generated with this platform makes these molecules difficult-to-express proteins compared to standard monoclonal antibodies (mAbs). This report describes how expression limitations of a bi-specific bi-paratopic BEAT antibody were improved in a holistic approach. An initial investigation allowed identification of a misbalance in the subunits composing the BEAT antibody as the potential root cause. This misbalance was then addressed by a signal peptide optimization, and the overall expression level was increased by the combination of two vector design elements on a single gene vector. Further improvements were made in the selection of cell populations and an upstream (USP) platform process was applied in combination with a cell culture temperature shift. This allowed titer levels of up to 6 g/L to be reached with these difficult-to-express proteins. Furthermore, a high-density seeding process was developed that allowed titers of around 11 g/L for the BEAT antibody, increasing the initial titer by a factor of 10. The approach was successfully applied to a tri-specific antibody with titer levels reaching 10 g/L. In summary, a platform process for difficult-to-express proteins was developed using molecular biology tools, cell line development, upstream process optimization and process intensification. • Holistic development overcoming expression limits in bi-/multispecific antibodies via mol. bio., cell line dev, process opt. • Molecular constructs in article enable very high expression levels, particularly beneficial for challenging proteins. • Report of a process allowing titers > 10 g/L (product) for bi- and multi-specific antibody formats. [ABSTRACT FROM AUTHOR]

The introduction of novel agents dramatically improved response and outcomes of multiple myeloma (MM) and led to a sharp decline in the use of allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Thus, recent guidelines do not recommend anymore allo-HSCT as consolidation in the first-line treatment of newly diagnosed MM, even in high-risk patients. In a relapsed/refractory setting, allo-HSCT is not routinely recommended but should only be performed within clinical trials in young and high-risk patients. Nonetheless, allo-HSCT still represents a potential curative approach that has been used for decades in the treatment of MM and plasma cell neoplasms with favorable results and may still represent a treatment option for carefully selected patients. Despite that promising results were obtained with CAR T-cell therapies and bispecific antibodies in triple- and penta-exposed/refractory MM, these patients will inevitably relapse. To date, less is known about outcomes of allo-HSCT in patients exposed to novel immunotherapeutic drugs. Therefore, allo-HSCT could represent a reasonable treatment choice for younger and high-risk patients who have relapsed after CAR T-cell therapies and bispecific antibodies as well as an alternative for patients not eligible to these treatments and in those countries where immunotherapies are not yet available. In the choice of conditioning, reduced intensity conditioning regimens are currently recommended for the lower toxicity and mortality. Moreover, the use of alternative donors, particularly haploidentical, has progressively increased in last years with results comparable to full matched donors. Finally, post-transplantation maintenance strategies are encouraged whenever feasible. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma (MM) represents the second most common hematological malignancy, but its diagnosis can be significantly delayed since symptoms are not specific and, mainly in the older population, alternate diagnoses can mimic MM. Bone marrow biopsy (evaluating the amount of proliferating myeloma cells) remains an essential procedure, but several imaging methods such as whole-body low-dose computed tomography, positron emission tomography or whole-body magnetic resonance have become crucial for the diagnosis and staging of MM, and are also taking on a prognostic role. MM is a clinically and biologically heterogeneous disease; therefore, with the aim to identify patients with different outcomes, some risk models such as ISS, R-ISS or R2-ISS have been proposed over time. However, the most recent attempts have been to establish individualized patient risk, integrating clinical, genomic and therapeutic data in order to personalize treatment and avoid overtreatment and toxicities. The outcome of multiple myeloma (MM) has significantly improved in the last few decades due to several factors such as new biological discoveries allowing to better stratify disease risk, development of more effective therapies and better management of side effects related to them. However, handling all these aspects requires an interdisciplinary approach involving multiple knowledge and collaboration of different specialists. The hematologist, faced with a patient with MM, must not only choose a treatment according to patient and disease characteristics but must also know when therapy needs to be started and how to monitor it during and after treatment. Moreover, he must deal not only with organ issues related to MM such as bone disease, renal failure or neurological disease but also with adverse events, often very serious, related to novel therapies, particularly new generation immunotherapies such as CAR T cell therapy and bispecific antibodies. In this review, we provide an overview on the newer MM diagnostic and monitoring strategies and on the main side effects of MM therapies, focusing on adverse events occurring during treatment with CAR T cells and bispecific antibodies. [ABSTRACT FROM AUTHOR]

Simple Summary: Diffuse large B cell lymphoma is the most common type of B cell neoplasm, and can be cured by traditional chemoimmunotherapy in 60–70% of cases. Relapsed/refractory patients usually have a dismal prognosis and most of them finally succumb to lymphoma. In the last decade, several new innovative therapies have been approved against DLBCL, targeting both surface antigens and the intracellular pathways of neoplastic B cells. Compared to standard chemotherapy, new monoclonal antibodies and engineered T cells have shown an increased response rate, progression-free survival and overall survival, but, on the other side of the coin, patients have been experiencing new kinds of toxicities, previously unknown, that clinicians have been learning to manage. Here, we review new drugs that are already approved or under investigation for DLBCL and the corresponding molecular target on lymphoma cells. Since the introduction of rituximab in the late 1990s, significant progress has been made in advancing targeted therapies for B cell lymphomas, improving patients' chance of being cured and clinicians' therapeutic armamentarium. A better understanding of disease biology and pathogenic pathways, coupled with refinements in immunophenotypic and molecular diagnostics, have been instrumental in these achievements. While traditional chemotherapy remains fundamental in most cases, concerns surrounding chemorefractoriness and cumulative toxicities, particularly the depletion of the hemopoietic reserve, underscore the imperative for personalized treatment approaches. Integrating targeted agents, notably monoclonal antibodies, alongside chemotherapy has yielded heightened response rates and prolonged survival. A notable paradigm shift is underway with innovative-targeted therapies replacing cytotoxic drugs, challenging conventional salvage strategies like stem cell transplantation. This review examines the landscape of emerging targets for lymphoma cells and explores innovative therapies for diffuse large B cell lymphoma (DLBCL). From Chimeric Antigen Receptor-T cells to more potent monoclonal antibodies, antibody–drug conjugates, bispecific antibodies, checkpoint inhibitors, and small molecules targeting intracellular pathways, each modality offers promising avenues for therapeutic advancement. This review aims to furnish insights into their potential implications for the future of DLBCL treatment strategies. [ABSTRACT FROM AUTHOR]

The Omicron subvariants BQ.1.1, XBB.1.5, and XBB.1.16 of SARS-CoV-2 are known for their adeptness at evading immune responses. Here, we isolate a neutralizing antibody, 7F3, with the capacity to neutralize all tested SARS-CoV-2 variants, including BQ.1.1, XBB.1.5, and XBB.1.16. 7F3 targets the receptor-binding motif (RBM) region and exhibits broad binding to a panel of 37 RBD mutant proteins. We develop the IgG-like bispecific antibody G7-Fc using 7F3 and the cross-neutralizing antibody GW01. G7-Fc demonstrates robust neutralizing activity against all 28 tested SARS-CoV-2 variants and sarbecoviruses, providing potent prophylaxis and therapeutic efficacy against XBB.1 infection in both K18-ACE and BALB/c female mice. Cryo-EM structure analysis of the G7-Fc in complex with the Omicron XBB spike (S) trimer reveals a trimer-dimer conformation, with G7-Fc synergistically targeting two distinct RBD epitopes and blocking ACE2 binding. Comparative analysis of 7F3 and LY-CoV1404 epitopes highlights a distinct and highly conserved epitope in the RBM region bound by 7F3, facilitating neutralization of the immune-evasive Omicron variant XBB.1.16. G7-Fc holds promise as a potential prophylactic countermeasure against SARS-CoV-2, particularly against circulating and emerging variants. In this study, the authors develop a potent bispecific antibody targeting two epitopes within the SARS-CoV-2 receptor binding domain and showing robust prophylactic and therapeutic efficacy against XBB.1 infection in mice. [ABSTRACT FROM AUTHOR]

An appropriately designed pharmacokinetic (PK) assay that is sensitive for antidrug antibody (ADA) impact on relevant exposure is an alternative strategy to understand the neutralizing potential of ADAs. However, guidance on how to develop such PK assays and how to confirm the functional ADA impact on exposure is missing. Here, the PK assay of a T-cell-engaging bispecific antibody, cibisatamab, was developed based on its mechanism of action (MoA). Using critical monoclonal anti-idiotypic (anti-ID) antibody positive controls as ADA surrogates, the impact on exposure was evaluated pre-clinically. In a phase I clinical trial (NCT02324257), initial data suggest that the combination of ADA and PK assays for correlation of the ADA response with cibisatamab exposure. To understand the neutralizing potential of patient-derived ADAs on drug activity, advanced ADA characterization has been performed. Structural binding analysis of ADAs to antibody domains of the drug and its impact on targeting were assessed. For this purpose, relevant patient ADA binding features were identified and compared with the specific monoclonal anti-ID antibody-positive controls. Comparable results of target binding inhibition and similar impacts on exposure suggest that the observed reduction of Cmax and Ctrough levels in patients is caused by the neutralizing potential of ADAs and allows a correlation between ADA response and loss of exposure. Therefore, the described study provides important functional aspects for the development of an appropriately designed PK assay for bispecific antibodies as an alternative option towards understanding the neutralizing ADA impact on exposure. [ABSTRACT FROM AUTHOR]

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with a high fatality rate of up to 30% caused by SFTS virus (SFTSV). However, no specific vaccine or antiviral therapy has been approved for clinical use. To develop an effective treatment, we isolated a panel of human monoclonal antibodies (mAbs). SF5 and SF83 are two neutralizing mAbs that recognize two viral glycoproteins (Gn and Gc), respectively. We found that their epitopes are closely located, and we then engineered them as several bispecific antibodies (bsAbs). Neutralization and animal experiments indicated that bsAbs display more potent protective effects than the parental mAbs, and the cryoelectron microscopy structure of a bsAb3 Fab-Gn-Gc complex elucidated the mechanism of protection. In vivo virus passage in the presence of antibodies indicated that two bsAbs resulted in less selective pressure and could efficiently bind to all single parental mAb-escape mutants. Furthermore, epitope analysis of the protective mAbs against SFTSV and RVFV indicated that they are all located on the Gn subdomain I, where may be the hot spots in the phleboviruses. Collectively, these data provide potential therapeutic agents and molecular basis for the rational design of vaccines against SFTSV infection. [ABSTRACT FROM AUTHOR]

Metastatic castrate resistant prostate cancer (mCRPC) continues to have poor survival rates due to limited treatment options. Bi-specific T cell engagers (BiTEs) are a promising class of novel immunotherapies with demonstrated success in haematological malignancies and melanoma. BiTEs developed for tumour associated antigens in prostate cancer have entered clinical testing. These trials have been hampered by high rates of treatment related adverse events, minimal or transient anti-tumour efficacy and generation of high titres of anti-drug antibodies. This paper aims to analyse the challenges faced by the different BiTE therapy constructs and the mCRPC tumour microenvironment that result in therapeutic resistance and identify possible strategies to overcome these issues. [ABSTRACT FROM AUTHOR]

Bispecific T-cell-engaging antibodies are a growing class of therapeutics with numerous molecules being tested in clinical trials and, currently, seven of them have received market approval. They are structurally complex and function as adaptors to redirect the cytotoxicity of T cells to kill tumor cells. T-cell-engaging bispecific antibodies can be generally divided into two categories: IgG/IgG-like and non-IgG-like formats. Different formats may have different intrinsic potencies and physiochemical properties, and comprehensive studies are needed to gain a better understanding of how the differences in formats impact on structural and functional characteristics. In this study, we designed and generated bispecific T-cell-engaging antibodies with IgG-like (DVD-Ig) and non-IgG (BiTE) formats. Both target the same pair of antigens (EGFR and CD3) to minimize the possible influence of targets on functional characterization. We performed a side-by-side comparison to assess differences in the physiochemical and biological properties of these two bispecific T-cellengaging antibodies using a variety of breast and ovarian cancer cell-based functional assays to delineate the structural-functional relationships and antitumor activities/potency. We found that the Fc portion of T-cell-engaging bispecific antibodies can significantly impact antigen binding activity, potency, and stability in addition to eliciting different mechanisms of action that contribute the killing of cancer cells. [ABSTRACT FROM AUTHOR]

The spread of cancer from organ to organ (metastasis) is responsible for the vast majority of cancer deaths; however, most current anti-cancer drugs are designed to arrest or reverse tumor growth without directly addressing disease spread. It was recently discovered that tumor cell-secreted interleukin-6 (IL-6) and interleukin-8 (IL-8) synergize to enhance cancer metastasis in a cell-density dependent manner, and blockade of the IL-6 and IL-8 receptors (IL-6R and IL-8R) with a novel bispecific antibody, BS1, significantly reduced metastatic burden in multiple preclinical mouse models of cancer. Bispecific antibodies (BsAbs), which combine two different antigen-binding sites into one molecule, are a promising modality for drug development due to their enhanced avidity and dual targeting effects. However, while BsAbs have tremendous therapeutic potential, elucidating the mechanisms underlying their binding and inhibition will be critical for maximizing the efficacy of new BsAb treatments. Here, we describe a quantitative, computational model of the BS1 BsAb, exhibiting how modeling multivalent binding provides key insights into antibody affinity and avidity effects and can guide therapeutic design. We present detailed simulations of the monovalent and bivalent binding interactions between different antibody constructs and the IL-6 and IL-8 receptors to establish how antibody properties and system conditions impact the formation of binary (antibody-receptor) and ternary (receptor-antibody-receptor) complexes. Model results demonstrate how the balance of these complex types drives receptor inhibition, providing important and generalizable predictions for effective therapeutic design. Author summary: Metastasis, the process of cancer cells spreading from one organ to another, leads to more severe disease and poorer outcomes for patients; unfortunately, many current drugs focus solely on halting tumor growth rather than directly addressing the spread of cancer cells. Two proteins that regulate the immune system, interleukin-6 and interleukin-8, work together to promote cancer spread when secreted by metastatic cancer cells. By blocking the receptors for these proteins, we can reduce cancer cell migration. Bispecific antibodies are an attractive therapeutic format because they can bind to two different targets at the same time, making them potentially more targeted (cell-type specific) and thus more effective than traditional monospecific antibodies. Here, we built a computational model of a novel bispecific antibody, BS1, that can bind to both an interleukin-6 receptor and an interleukin-8 receptor, and thus targets the interleukin-6/interleukin-8 system for the prevention of metastasis. We compare our model simulations of BS1 to simulations of antibodies that bind only one receptor, and thereby demonstrate how the bispecific characteristic of antibodies affects target inhibition. This provides important insights into the optimal design for BS1 and other bispecific therapeutics. [ABSTRACT FROM AUTHOR]

Introduction: Novel therapies for 3L+ relapsed/refractory (r/r) follicular lymphoma (FL) have been approved recently by the US Food and Drug Administration including anti-CD19 CAR-T therapies such as axicabtagene ciloleucel (axi-cel) and CD20 × CD3 T-cell-engaging bispecific monoclonal antibodies such as mosunetuzumab (mosun). The objective of this study was to assess the cost-effectiveness of axi-cel compared to mosun in 3L+ r/r FL patients from a US third-party payer perspective. Methods: A three-state (progression-free, progressed disease, and death) partitioned-survival model was used to compare two treatments over a lifetime horizon in a hypothetical cohort of US adults (age =18) receiving 3L+ treatment for r/r FL. ZUMA-5 and GO29781 trial data were used to inform progression-free survival (PFS) and overall survival (OS). Mosun survival was modeled via hazard ratios (HRs) applied to axi-cel survival curves. The PFS HR value was estimated via a matching-adjusted indirect comparison (MAIC) based on mosun pseudo-individual patient data and adjusted axi-cel data to account for trial populations differences. One-way sensitivity analysis (OWSA) and probabilistic sensitivity analyses (PSA) were conducted. Scenario analyses included: 1) the mosun HRs were applied to the weighted (adjusted) ZUMA-5 24-month data to most exactly reflect the MAIC, 2) mosun HR values were applied to axi-cel 48-month follow-up data, and 3) recent axi-cel health state utility values in diffuse large B-cell lymphoma patients. Results: The analysis estimated increases of 1.82 LY and 1.89 QALY for axi-cel compared to mosun. PFS for axi-cel patients was 6.42 LY vs. 1.60 LY for mosun. Increase of $257,113 in the progression-free state was driven by one-time axi-cel treatment costs. Total incremental costs for axi-cel were $204,377, resulting in an ICER of $108,307/QALY gained. The OWSA led to ICERs ranging from $240,255 to $75,624, with all but two parameters falling below $150,000/QALY. In the PSA, axi-cel had an 64% probability of being cost-effective across 5,000 iterations using a $150,000 willingness-to-pay threshold. Scenarios one and two resulted in ICERs of $105,353 and $102,695, respectively. Discussion: This study finds that axi-cel is cost-effective compared to mosun at the commonly cited $150,000/QALY US willingness-to-pay threshold, with robust results across a range of sensitivity analyses accounting for parameter uncertainty. [ABSTRACT FROM AUTHOR]

The optimization of the affinity of monoclonal antibodies is crucial for the development of drug candidates, as it can impact the efficacy of the drug and, thus, the dose and dosing regimen, limit adverse effects, and reduce therapy costs. Here, we present the affinity maturation of an EGFR×PD-L1 Two-in-One antibody for EGFR binding utilizing site-directed mutagenesis and yeast surface display. The isolated antibody variants target EGFR with a 60-fold-improved affinity due to the replacement of a single amino acid in the CDR3 region of the light chain. The binding properties of the Two-in-One variants were confirmed using various methods, including BLI measurements, real-time antigen binding measurements on surfaces with a mixture of both recombinant proteins and cellular binding experiments using flow cytometry as well as real-time interaction cytometry. An AlphaFold-based model predicted that the amino acid exchange of tyrosine to glutamic acid enables the formation of a salt bridge to an arginine at EGFR position 165. This easily adaptable approach provides a strategy for the affinity maturation of bispecific antibodies with respect to the binding of one of the two antigens. [ABSTRACT FROM AUTHOR]

Background: Glofitamab is a bispecific antibody with promise for treating relapsed/refractory B‐cell lymphoma according to a phase 1/2 clinical trial. This study examined its real‐world effectiveness. Methods: This was an investigator‐initiated, multicenter retrospective study including 34 patients who had relapsed/refractory B‐cell lymphomas after at least three prior lines of therapy and received glofitamab monotherapy in a compassionate use program in Taiwan between January 2021 and October 2022. Results: At a median follow‐up of 15.9 months, 56% of patients responded to glofitamab and 23% achieved complete remission. Response to the previous line of therapy significantly correlated with response to glofitamab (p =.020). Most responses were durable; only five out of the 19 responders had documented disease recurrence at the data cutoff date. The estimated progression‐free survival (PFS) was 3.2 months, and the estimated 1‐year PFS was 33% for the entire cohort. PFS was better for responders than nonresponders (median PFS, 16.9 vs. 1.8 months; 1‐year PFS, 60% vs. 0%). Forty‐three cytokine release syndrome (CRS) events were observed, three of which were grade 3; all were manageable without glofitamab discontinuation. No immune effector cell–associated neurotoxicity was reported. Among seven hepatitis B virus (HBV) carriers (six had antiviral prophylaxis) and 14 patients with remote HBV (four had antiviral prophylaxis), no HBV reactivation was observed. Conclusions: In this real‐world cohort, glofitamab exhibited effectiveness comparable to trial results without excessive CRS or new safety issues. With appropriate prophylaxis, glofitamab‐treated patients with chronic or remote HBV infection are unlikely to experience virus reactivation. [ABSTRACT FROM AUTHOR]

Aim: To describe the biomarker strategy that was applied to select survodutide (BI 456906), BI 456908 and BI 456897 from 19 dual glucagon receptor (GCGR)/ glucagon‐like peptide‐1 receptor (GLP‐1R) agonists for in‐depth pharmacological profiling, which led to the qualification of survodutide as the clinical development candidate. Materials and Methods: Potencies to increase cyclic adenosine monophosphate (cAMP) were determined in Chinese hamster ovary (CHO)‐K1 cells stably expressing human GCGR and GLP‐1R. Agonism for endogenously expressed receptors was investigated in insulinoma cells (MIN6) for mouse GLP‐1R, and in rat primary hepatocytes for the GCGR. In vivo potencies to engage the GLP‐1R or GCGR were determined, measuring improvement in oral glucose tolerance (30 nmol/kg) and increase in plasma fibroblast growth factor‐21 (FGF21) and liver nicotinamide N‐methyltransferase (NNMT) mRNA expression (100 nmol/kg), respectively. Body weight‐ and glucose‐lowering efficacies were investigated in diet‐induced obese (DIO) mice and diabetic db/db mice, respectively. Results: Upon acute dosing in lean mice, target engagement biomarkers for the GCGR and GLP‐1R demonstrated a significant correlation (Spearman correlation coefficient with p < 0.05) to the in vitro GCGR and GLP‐1R potencies for the 19 dual agonists investigated. Survodutide, BI 456908 and BI 456897 were selected for in‐depth pharmacological profiling based on the significant improvement in acute oral glucose tolerance achieved (area under the curve [AUC] of 54%, 57% and 60% vs. vehicle) that was comparable to semaglutide (AUC of 45% vs. vehicle), while showing different degrees of in vivo GCGR engagement, as determined by hepatic NNMT mRNA expression (increased by 15‐ to 17‐fold vs. vehicle) and plasma FGF21 concentrations (increased by up to sevenfold vs. vehicle). In DIO mice, survodutide (30 nmol/kg/once daily), BI 456908 (30 nmol/kg/once daily) and BI 456897 (10 nmol/kg/once daily) achieved a body weight‐lowering efficacy from baseline of 25%, 27% and 26%, respectively. In db/db mice, survodutide and BI 456908 (10 and 20 nmol/kg/once daily) significantly lowered glycated haemoglobin (0.4%–0.6%); no significant effect was observed for BI 456897 (3 and 7 nmol/kg/once daily). Conclusions: Survodutide was selected as the clinical candidate based on its balanced dual GCGR/GLP‐1R pharmacology, engaging the GCGR for robust body weight‐lowering efficacy exceeding that of selective GLP‐1R agonists, while achieving antidiabetic efficacy that was comparable to selective GLP‐1R agonism. Survodutide is currently being investigated in Phase 3 clinical trials in people living with obesity. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) may be cured with anti-CD20 based chemoimmunotherapy in the majority of cases, however, relapsed/refractory disease occurs in 30–40% patients, and despite significant recent therapeutic advances, continues to represent an unmet clinical need. Bispecific antibodies represent a novel class of therapy currently in development for relapsed/refractory B-cell lymphoma. This review discusses the background clinical need, mechanism of action, and clinical data including efficacy and toxicity for bispecific antibodies in DLBCL, focusing on the most advanced class in development; CD20 targeting T-cell engaging antibodies. Emerging possibilities for future use of bispecific antibodies is also discussed, including novel and cytotoxic combination regimens in relapsed and first-line settings. [ABSTRACT FROM AUTHOR]

Non-small-cell lung cancer (NSCLC) frequently harbors mutations in the epidermal growth factor receptor (EGFR), with exon 20 insertions comprising 1–10% of these mutations. EGFR exon 20 insertions are less responsive to conventional tyrosine kinase inhibitors (TKIs), leading to the development of targeted agents. This review explores key therapeutic agents, such as Amivantamab, Mobocertinib, Poziotinib, Zipalertinib, and Sunvozertinib, which have shown promise in treating NSCLC with EGFR exon 20 insertions. Amivantamab, a bispecific antibody-targeting EGFR and c-MET, demonstrates significant efficacy, particularly when combined with chemotherapy. Mobocertinib, a TKI, selectively targets EGFR exon 20 mutations but faces limitations in efficacy. Poziotinib, another oral TKI, shows mixed results due to mutation-specific responses. Zipalertinib and Sunvozertinib have emerged as potent TKIs with promising clinical data. Despite these advances, challenges in overcoming resistance mutations and improving central nervous system penetration remain. Future research should focus on optimizing first-line combination therapies and enhancing diagnostic strategies for comprehensive mutation profiling. [ABSTRACT FROM AUTHOR]

Bispecific antibodies (BsAbs) are an effective treatment used in relapsed or refractory multiple myeloma. Despite a well-tolerated safety profile, infectious events appear to be frequent in clinical trials. Real-world data on epidemiology, characteristics, risk factors, and outcomes of infections in patients treated with BsAb are still needed. A retrospective, multicentre study in BsAb-treated patients with multiple myeloma was performed in 14 French centres from December 2020 to February 2023. The primary objective was to describe the incidence of infections that required hospitalization, specific treatment, or adaptation in BsAb administration. Among 229 patients with multiple myeloma treated with BsAb, 153 (67%) received teclistamab, 47 (20%) received elranatamab, and 29 (13%) talquetamab. We reported a total of 234 infections, including 123 (53%) of grade of ≥3. Predominant infections affected the respiratory tract (n = 116, 50%) followed by bacteraemias (n = 36, 15%). The hospitalization rate was 56% (n = 131), and 20 (9%) infections resulted in death. Global cumulative incidence of the first infection was 70% in all patients, 73% in patients treated with B-cell maturation antigen-targeting, and 51% with GPRC5D-targeting BsAb. In univariate analyses, corticosteroids for cytokine release syndrome (CRS)/immune effector cell-associated neurotoxicity syndrome (ICANS) were associated with a higher risk of first infection (HR = 2.13; 95% CI, 1.38–3.28), whereas GPRC5D-targeting BsAb and anti-bacterial prophylaxis were associated with a lower risk (HR = 0.53; 95% CI, 0.3–0.94 and HR = 0.65; 95% CI, 0.46–0.9). Fine and Gray multivariate model found that only corticosteroids for CRS/ICANS were correlated with a higher risk of first infection (HR = 2.01; 95% CI, 1.27–3.19). The implementation of preventive measures that aim to mitigate the risk of infection under BsAb is pivotal, notably in patients who received corticosteroids for CRS/ICANS. [ABSTRACT FROM AUTHOR]

The treatment of relapsed and refractory multiple myeloma has improved substantially in the last 5–10 years based on the development and use of several novel classes of drugs and drug combinations. These advances have led to improvements in progression-free and overall survival as well as quality of life. The general tendency has been to advance drugs/combinations that have performed well in advanced disease to the earlier line settings (frontline, first/early relapse). There are several triplet drug combinations that, when used as part of first or early relapse, can provide remission durations of 3 years or longer. More recently, impressive responses have been seen with the use of targeted immunotherapeutics (chimeric antigen receptor T-cells and bispecific antibodies) in heavily pretreated patients with MM. These treatments, however, have been associated with some new and occasionally severe toxicities, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and severe infections, including opportunistic infections and profound cytopenias. These potential toxicities bring into question whether these immune-targeting drugs should remain as late-line therapeutics or whether the high single-agent overall response rates mandate that these agents be used in earlier line settings. Herein, the authors provide a point and counterpoint about the future use of these agents. [ABSTRACT FROM AUTHOR]

Improvement in the therapeutics for multiple myeloma (MM) has been continuously developed owing to the application of novel drugs and technologies in the last 20 years. The standard first-line therapy for MM consists of a three-drug induction regimen based on immunomodulatory drugs and proteasome inhibitors combined with autologous stem cell transplantation. However, MM remains incurable; therefore, therapies for relapsed/refractory MM (RRMM) are emerging and evolving rapidly. This study aimed to summarize and review the results of RRMM trials over the past 5 years to provide a holistic overview and insights for practitioners in related fields and to provide additional ideas for clinical trialists. This study shows that daratumumab and isatuximab continue to significantly advance as treatment options. Additionally, novel antibody drugs, such as elotuzumab and selinexor, as well as bispecific antibodies, teclistamab and talquetamab, are currently undergoing clinical research with promising outcomes. However, chimeric antigen receptor-T cell therapy targeting B-cell maturation antigen remains the optimal approach for MM treatment. [ABSTRACT FROM AUTHOR]

Despite an important therapeutic arsenal targeting the ErbB family, patients inevitably develop drug resistance, mediated by acquired mutations and crosstalk pathway activation. Bispecific antibodies emerge as enticing ErbB therapeutics, mainly due to their multitarget involvement to help overcome drug resistance. Targeted protein degradation (TPD) strategies are promising new approaches to restrict ErbB family oncogenicity. Peptides and nanobodies are ever-evolving fields in oncology, offering small molecules that bypass major constraints in tumors and representing suitable biotherapeutics and diagnostic tools for ErbB-driven cancer treatment. EGF-like domain-containing proteins within the tumor microenvironment have recently received attention due to their direct interaction with ErbB family and involvement in cancer progression, rendering them promising anticancer targets. The epidermal growth factor receptor (EGFR) family is a class of transmembrane proteins, highly regarded as anticancer targets due to their pivotal role in various malignancies. Standard cancer treatments targeting the ErbB receptors include tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs). Despite their substantial survival benefits, the achievement of curative outcomes is hindered by acquired resistance. Recent advancements in anti-ErbB approaches, such as inhibitory peptides, nanobodies, targeted-protein degradation strategies, and bispecific antibodies (BsAbs), aim to overcome such resistance. More recently, emerging insights into the cell surface interactome of the ErbB family open new avenues for modulating ErbB signaling by targeting specific domains of ErbB partners. Here, we review recent progress in ErbB targeting and elucidate emerging paradigms that underscore the significance of EGF domain-containing proteins (EDCPs) as new ErbB-targeting pathways. [ABSTRACT FROM AUTHOR]

This article explores the significance of dose optimization in the development of oncology drugs and the importance of a patient-centered approach. It discusses the efforts of scientific organizations like Friends of Cancer Research and the American Society of Clinical Oncology in addressing this issue. The article presents the findings of a survey conducted by the American Society for Clinical Pharmacology and Therapeutics on oncology dose optimization, including the use of pharmacodynamic biomarkers and different approaches for dose selection. It also discusses translational development strategies and the role of clinical pharmacology in driving progress in dose optimization. The article concludes by emphasizing the need for patient-focused dose optimization and the transformation of clinical trial paradigms in oncology. Additionally, it discusses the use of quantitative clinical pharmacology and Bayesian trial designs in optimizing dosing regimens, highlighting the importance of model-based analyses and the integration of preclinical, clinical, and biomarker data. The article also emphasizes the need for collaboration between pharmacologists and statisticians to maximize the benefits of Bayesian frameworks. It draws parallels between HIV drug discovery and oncology, highlighting the potential for biomarkers and early-stage investment to improve outcomes. The text concludes by calling for further research and discussion to advance patient-focused evidence generation in oncology therapy development. [Extracted from the article]

Mosunetuzumab (Mosun) is a CD20xCD3 T‐cell engaging bispecific antibody that redirects T cells to eliminate malignant B cells. The approved step‐up dose regimen of 1/2/60/30 mg IV is designed to mitigate cytokine release syndrome (CRS) and maximize efficacy in early cycles. A population pharmacokinetic (popPK) model was developed from 439 patients with relapsed/refractory B‐Cell Non‐Hodgkin lymphoma receiving Mosun IV monotherapy, including fixed dosing (0.05–2.8 mg IV every 3 weeks (q3w)) and Cycle 1 step‐up dosing groups (0.4/1/2.8–1/2/60/30 mg IV q3w). Prior to Mosun treatment, ~50% of patients had residual levels of anti‐CD20 drugs (e.g., rituximab or obinutuzumab) from prior treatment. CD20 receptor binding dynamics and rituximab/obinutuzumab PK were incorporated into the model to calculate the Mosun CD20 receptor occupancy percentage (RO%) over time. A two‐compartment model with time‐dependent clearance (CL) best described the data. The typical patient had an initial CL of 1.08 L/day, transitioning to a steady‐state CL of 0.584 L/day. Statistically relevant covariates on PK parameters included body weight, albumin, sex, tumor burden, and baseline anti‐CD20 drug concentration; no covariate was found to have a clinically relevant impact on exposure at the approved dose. Mosun CD20 RO% was highly variable, attributed to the large variability in residual baseline anti‐CD20 drug concentration (median = 10 μg/mL). The 60 mg loading doses increased Mosun CD20 RO% in Cycle 1, providing efficacious exposures in the presence of the competing anti‐CD20 drugs. PopPK model simulations, investigating Mosun dose delays, informed treatment resumption protocols to ensure CRS mitigation. [ABSTRACT FROM AUTHOR]

T cell-redirecting bispecific antibodies are specifically designed to bind to tumor-associated antigens, thereby engaging with CD3 on the T cell receptor. This linkage between tumor cells and T cells actively triggers T cell activation and initiates targeted killing of the identified tumor cells. These antibodies have emerged as one of the most promising avenues within tumor immunotherapy. However, despite success in treating hematological malignancies, significant advancements in solid tumors have yet to be explored. In this review, we aim to address the critical challenges associated with T cell-redirecting bispecific antibodies and explore novel strategies to overcome these obstacles, with the ultimate goal of expanding the application of this therapy to include solid tumors. This review summarizes the developments of T cell-redirecting bispecific antibodies, with a focus on therapy-associated key toxicities, challenges and future perspectives. [Display omitted] [ABSTRACT FROM AUTHOR]

Modern immunotherapy approaches are revolutionizing the treatment scenario of relapsed/refractory (RR) multiple myeloma (MM) patients, providing an opportunity to reach deep level of responses and extend survival outcomes. Antibody-drug conjugates (ADCs) and T-cell redirecting treatments, including bispecific antibodies (BsAbs) and chimeric antigen receptor (CAR) T cells therapy, have been recently introduced in the treatment of RRMM. Some agents have already received regulatory approval, while newer constructs, novel combinations, and applications in earlier lines of therapy are currently being explored. This review discusses the current landscape and possible development of ADCs, BsAbs and CAR-T cells immunotherapies. ADCs, BsAbs, and CAR-T therapy have demonstrated substantial activity in heavily pretreated, triple-class exposed (TCE) MM patients, and T-cell redirecting treatments represent new standards of care after third (European Medicines Agency, EMA), or fourth (Food and Drug Administration, FDA), line of therapy. All these three immunotherapies carry advantages and disadvantages, with different accessibility and new toxicities that require appropriate management and guidelines. Multiple on-going programs include combinations therapies and applications in earlier lines of treatment, as well as the development of novel agents or construct to enhance potency, reduce toxicity and facilitate administration. Sequencing is a challenge, with few data available and mechanisms of resistance still to be unraveled. [ABSTRACT FROM AUTHOR]

Oxidative stress refers to the overproduction of reactive oxygen species and is often associated with numerous pathological conditions. Superoxide dismutase (SOD) is a widely used enzyme for evaluating oxidative stress, with numerous methods being developed for its detection in biological specimens like blood, urine, and saliva. In this study, a simple metal-assisted chemical etching method was employed for the fabrication of nanostructured silicon surfaces decorated with either silver dendrites or silver aggregates. Those surfaces were used as substrates for the immunochemical determination of SOD in synthetic saliva through surface-enhanced Raman spectroscopy (SERS) and surface-enhanced fluorescence (SEF). The immunoassay was based on a 3-step competitive assay format, which included, after the immunoreaction with the specific anti-SOD antibody, a reaction with a biotinylated secondary antibody and streptavidin. Streptavidin labeled with peroxidase was used in combination with a precipitating tetramethylbenzidine substrate for detection through SERS, whereas for SEF measurements, streptavidin labeled with the fluorescent dye Rhodamine Red-X was utilized. Both immunoassays were sensitive, with a detection limit of 0.01 μg/mL and a linear dynamic range from 0.03 to 3.3 μg/mL, enabling the evaluation of the oxidative stress status of an organism. [ABSTRACT FROM AUTHOR]

B‐cell maturation antigen (BCMA)‐targeting immunotherapies (e.g., chimeric antigen receptor T cells (CAR‐T) and bispecific antibodies (BsAbs)) have achieved remarkable clinical responses in patients with relapsed and/or refractory multiple myeloma (RRMM). Their use is accompanied by exaggerated immune responses related to T‐cell activation and cytokine elevations leading to cytokine release syndrome (CRS) in some patients, which can be potentially life‐threatening. However, systematic evaluation of the risk of CRS with BCMA‐targeting BsAb and CAR‐T therapies, and comparisons across different routes of BsAb administration (intravenous (i.v.) vs. subcutaneous (s.c.)) have not previously been conducted. This study utilized a meta‐analysis approach to compare the CRS profile in BCMA‐targeting CAR‐T vs. BsAb immunotherapies administered either i.v. or s.c. in patients with RRMM. A total of 36 studies including 1,560 patients with RRMM treated with BCMA‐targeting CAR‐T and BsAb therapies were included in the analysis. The current analysis suggests that compared with BsAbs, CAR‐T therapies were associated with higher CRS incidences (88% vs. 59%), higher rates of grade ≥ 3 CRS (7% vs. 2%), longer CRS duration (5 vs. 2 days), and more prevalent tocilizumab use (44% vs. 25%). The proportion of CRS grade ≥ 3 may also be lower (0% vs. 4%) for BsAb therapies administered via the s.c. (3 studies, n = 311) vs. i.v. (5 studies, n = 338) route. This meta‐analysis suggests that different types of BCMA‐targeting immunotherapies and administration routes could result in a range of CRS incidence and severity that should be considered while evaluating the benefit–risk profiles of these therapies. [ABSTRACT FROM AUTHOR]

Recently, several bispecific antibodies (BsAbs) have been approved for the treatment of relapsed multiple myeloma (MM) after early phase trials in heavily pre-treated patients demonstrated high response rates and impressive progression-free survival with monotherapy. These BsAbs provide crucial treatment options for relapsed patients and challenging decisions for clinicians. Evidence on the optimal patient population, treatment sequence, and duration of these therapeutics is unknown and subject to active investigation. While rates of cytokine release syndrome and neurotoxicity appear to be lower with BsAbs than with CAR T-cells, morbidity from infection is high and novel pathways of treatment resistance arise from the longitudinal selection pressure of chronic BsAb therapy. Lastly, a wealth of novel T-cell engagers with unique antibody-structures and antigenic targets are under active investigation with promising early outcome data. In this review, we examine the mechanism of action, therapeutic targets, combinational approaches, sequencing and mechanisms of disease relapse for BsAbs in MM.

The article discusses the impact of emicizumab on the clinical validation of new therapies for haemophilia A. Emicizumab, a bispecific antibody, has revolutionized the management of patients with inhibitors against factor VIII, providing efficient prophylaxis. However, its widespread adoption may hinder the development and validation of other therapeutic agents, potentially impacting global patient recruitment in clinical studies. The article emphasizes the importance of maintaining patient recruitment in high-quality research settings to support the development of future innovations in haemophilia treatment. [Extracted from the article]