Search

Immune checkpoint mechanisms are important molecular cell systems that maintain tolerance toward autoantigens in order to prevent immunity-mediated accidental damage. It is well known that cancer cells may exploit these molecular and cellular mechanisms to escape recognition and elimination by immune cells. Programmed cell death protein-1 (PD-1) and its natural ligand programmed cell death ligand-1 (PD-L1) form the PD-L1/PD-1 axis, a well-known immune checkpoint mechanism, which is considered an interesting target in cancer immunotherapy. In fact, the expression of PD-L1 was found in various solid malignancies and the overactivation of PD-L1/PD-1 axis results in a poor patient survival rate. Breaking PD-L1/PD-1 axis, by blocking either the cancer side or the immune side of the axis, is currently used as anti-cancer strategy to re-establish a tumor-specific immune response. For this purpose, several blocking antibodies are now available. To date, three anti-PD-L1 antibodies have been approved by the FDA, namely atezolizumab, durvalumab and avelumab. The main advantages of anti-PD-L1 antibodies arise from the overexpression of PD-L1 antigen by a high number of tumor cells, also deriving from different tissues; this makes anti-PD-L1 antibodies potential pan-specific anti-cancer molecules. Despite the good results reported in clinical trials with anti-PD-L1 antibodies, there is a significant number of patients that do not respond to the therapy. In fact, it should be considered that, in some neoplastic patients, reduced or absent infiltration of cytotoxic T cells and natural killer cells in the tumor microenvironment or presence of other immunosuppressive molecules make immunotherapy with anti-PD-L1 blocking antibodies less effective. A strategy to improve the efficacy of antibodies is to use them as carriers for toxic payloads (toxins, drugs, enzymes, radionuclides, etc.) to form immunoconjugates. Several immunoconjugates have been already approved by FDA for treatment of malignancies. In this review, we focused on PD-L1 targeting antibodies utilized as carrier to construct immunoconjugates for the potential elimination of neoplastic cells, expressing PD-L1. A complete examination of the literature regarding anti-PD-L1 immunoconjugates is here reported, describing the results obtained in vitro and in vivo. The real potential of anti-PD-L1 antibodies as carriers for toxic payload delivery is considered and extensively discussed.

Diffuse intrinsic pontine glioma (DIPG), a rare pediatric brain tumor, afflicts approximately 350 new patients each year in the United States. DIPG is noted for its lethality, as fewer than 1% of patients survive to five years. Multiple clinical trials involving chemotherapy, radiotherapy, and/or targeted therapy have all failed to improve clinical outcomes. Recently, high-throughput sequencing of a cohort of DIPG samples identified potential therapeutic targets, including interleukin 13 receptor subunit alpha 2 (IL13Rα2) which was expressed in multiple tumor samples and comparably absent in normal brain tissue, identifying IL13Rα2 as a potential therapeutic target in DIPG. In this work, we investigated the role of IL13Rα2 signaling in progression and invasion of DIPG and viability of IL13Rα2 as a therapeutic target through the use of immunoconjugate agents. We discovered that IL13Rα2 stimulation via canonical ligands demonstrates minimal impact on both the cellular proliferation and cellular invasion of DIPG cells, suggesting IL13Rα2 signaling is non-essential for DIPG progression in vitro. However, exposure to an anti-IL13Rα2 antibody–drug conjugate demonstrated potent pharmacological response in DIPG cell models both in vitro and ex ovo in a manner strongly associated with IL13Rα2 expression, supporting the potential use of targeting IL13Rα2 as a DIPG therapy. However, the tested ADC was effective in most but not all cell models, thus selection of the optimal payload will be essential for clinical translation of an anti-IL13Rα2 ADC for DIPG. Supplementary Information The online version contains supplementary material available at 10.1186/s40478-021-01184-9.

Targeted therapy has been recently highlighted due to the reduction of side effects and improvement in overall efficacy and survival from different types of cancers. Considering the approval of many monoclonal antibodies in the last twenty years, cancer treatment can be accomplished by the combination of monoclonal antibodies and small molecule chemotherapeutics. Thus, strategies to combine both drugs in a single administration system are relevant in the clinic. In this context, two strategies are possible and will be further discussed in this review: antibody-drug conjugates (ADCs) and antibody-functionalized nanoparticles. First, it is important to better understand the possible molecular targets for cancer therapy, addressing different antigens that can selectively bind to antibodies. After selecting the best target, ADCs can be prepared by attaching a cytotoxic drug to an antibody able to target a cancer cell antigen. Briefly, an ADC will be formed by a monoclonal antibody (MAb), a cytotoxic molecule (cytotoxin) and a chemical linker. Usually, surface-exposed lysine or the thiol group of cysteine residues are used as anchor sites for linker-drug molecules. Another strategy that should be considered is antibody-functionalized nanoparticles. Basically, liposomes, polymeric and inorganic nanoparticles can be attached to specific antibodies for targeted therapy. Different conjugation strategies can be used, but nanoparticles coupling between maleimide and thiolated antibodies or activation with the addition of ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC)/ N-hydroxysuccinimide (NHS) (1:5) and further addition of the antibody are some of the most used strategies. Herein, molecular targets and conjugation strategies will be presented and discussed to better understand the in vitro and in vivo applications presented. Also, the clinical development of ADCs and antibody-conjugated nanoparticles are addressed in the clinical development section. Finally, due to the innovation related to the targeted therapy, it is convenient to analyze the impact on patenting and technology. Information related to the temporal evolution of the number of patents, distribution of patent holders and also the number of patents related to cancer types are presented and discussed. Thus, our aim is to provide an overview of the recent developments in immunoconjugates for cancer targeting and highlight the most important aspects for clinical relevance and innovation.

Summary Background PD-1 blockade via pembrolizumab monotherapy has shown antitumour activity and toxicity in patients with relapsed or refractory classical Hodgkin lymphoma. Here, we present interim analyses from the KEYNOTE-204 study evaluating pembrolizumab versus brentuximab vedotin for relapsed or refractory classical Hodgkin lymphoma. Methods In this randomised, open-label, phase 3 study, patients aged 18 years or older with relapsed or refractory classical Hodgkin lymphoma with measurable disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 who were ineligible for or had relapsed after autologous haematopoietic stem-cell transplantation (HSCT) were enrolled at 78 hospitals and cancer centres in 20 countries and territories. Patients were randomly assigned (1:1) with an interactive voice response system to pembrolizumab 200 mg intravenously every 3 weeks or brentuximab vedotin 1·8 mg/kg intravenously every 3 weeks. Randomisation was stratified by previous autologous HSCT and status after front-line therapy. Results from the second interim analysis are presented here, with a database cutoff of Jan 16, 2020. The dual primary endpoints assessed in the intention-to-treat population were progression-free survival as assessed by blinded independent central review, and overall survival (not analysed at this interim analysis). Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT02684292. Recruitment for this trial is closed. Findings Between July 8, 2016, and July 13, 2018, 151 patients were randomly assigned to pembrolizumab and 153 to brentuximab vedotin. After a median time from randomisation to data cutoff of 25·7 months (IQR 23·4–33·0), median progression-free survival was 13·2 months (95% CI 10·9–19·4) for pembrolizumab versus 8·3 months (5·7–8·8) for brentuximab vedotin (hazard ratio 0·65 [95% CI 0·48–0·88]; p=0·0027). The most common grade 3–5 treatment-related adverse events were pneumonitis (six [4%] of 148 patients in the pembrolizumab group vs one [1%] of 152 patients in the brentuximab vedotin group), neutropenia (three [2%] vs 11 [7%]), decreased neutrophil count (one [1%] vs seven [5%]), and peripheral neuropathy (one [1%] vs five [3%]). Serious treatment-related adverse events occurred in 24 (16%) of 148 patients receiving pembrolizumab and 16 (11%) of 152 patients receiving brentuximab vedotin. One treatment-related death due to pneumonia occurred in the pembrolizumab group. Interpretation Pembrolizumab showed statistically significant and clinically meaningful improvement in progression-free survival compared with brentuximab vedotin, with safety consistent with previous reports. These data support pembrolizumab as the preferred treatment option for patients with relapsed or refractory classical Hodgkin lymphoma who have relapsed post-autologous HSCT or are ineligible for autologous HSCT. Funding Merck Sharp & Dohme Corp (a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA). Translation For the Portuguese translation of the Article see Supplementary Materials section.

Delta-like ligand 3 (DLL3) is a therapeutic target for the treatment of small cell lung cancer, neuroendocrine prostate cancer, and isocitrate dehydrogenase mutant glioma. In the clinic, DLL3-targeted 89Zr-immunoPET has the potential to aid in the assessment of disease burden and facilitate the selection of patients suitable for therapies that target the antigen. The overwhelming majority of 89Zr-labeled radioimmunoconjugates are synthesized via the random conjugation of desferrioxamine (DFO) to lysine residues within the immunoglobulin. While this approach is admittedly facile, it can produce heterogeneous constructs with suboptimal in vitro and in vivo behavior. In an effort to circumvent these issues, we report the development and preclinical evaluation of site-specifically labeled radioimmunoconjugates for DLL3-targeted immunoPET. To this end, we modified a cysteine-engineered variant of the DLL3-targeting antibody SC16-MB1 with two thiol-reactive variants of DFO: one bearing a maleimide moiety (Mal-DFO) and the other containing a phenyloxadiazolyl methyl sulfone group (PODS-DFO). In an effort to obtain immunoconjugates with a DFO-to-antibody ratio (DAR) of 2, we explored both the reduction of the antibody with tris(2-carboxyethyl) phosphine (TCEP) as well as the use of a combination of glutathione and arginine as reducing and stabilizing agents, respectively. While exerting control over the DAR of the immunoconjugate proved cumbersome using TCEP, the use of glutathione and arginine enabled the selective reduction of the engineered cysteines and thus the formation of homogeneous immunoconjugates. A head-to-head comparison of the resulting 89Zr-radioimmunoconjugates in mice bearing DLL3-expressing H82 xenografts revealed no significant differences in tumoral uptake and showed comparable radioactivity concentrations in most healthy nontarget organs. However, 89Zr-DFOPODS-DAR2SC16-MB1 produced 30% lower uptake (3.3 ± 0.5 %ID/g) in the kidneys compared to 89Zr-DFOMal-DAR2SC16-MB1 (4.7 ± 0.5 %ID/g). In addition, H82-bearing mice injected with a 89Zr-labeled isotype-control radioimmunoconjugate synthesized using PODS exhibited ∼40% lower radioactivity in the kidneys compared to mice administered its maleimide-based counterpart. Taken together, these results demonstrate the improved in vivo performance of the PODS-based radioimmunoconjugate and suggest that a stable, well-defined DAR2 radiopharmaceutical may be suitable for the clinical immunoPET of DLL3-expressing cancers.

Tissue factor (TF), the trigger protein of the extrinsic blood coagulation cascade, is abundantly expressed in various cancers including gastric cancer. Anti‐TF monoclonal antibodies (mAbs) capable of targeting cancers have been successfully applied to armed antibodies such as antibody‐drug conjugates (ADCs) and molecular imaging probes. We prepared an anti‐TF mAb, clone 1084, labeled with astatine‐211 (211At), as a promising alpha emitter for cancer treatment. Alpha particles are characterized by high linear energy transfer and a range of 50‐100 µm in tissue. Therefore, selective and efficient tumor accumulation of alpha emitters results in potent antitumor activities against cancer cells with minor effects on normal cells adjacent to the tumor. Although the 211At‐conjugated clone 1084 (211At‐anti‐TF mAb) was disrupted by an 211At‐induced radiochemical reaction, we demonstrated that astatinated anti‐TF mAbs eluted in 0.6% or 1.2% sodium ascorbate (SA) solution were protected from antibody denaturation, which contributed to the maintenance of cellular binding activities and cytocidal effects of this immunoconjugate. Although body weight loss was observed in mice administered a 1.2% SA solution, the loss was transient and the radioprotectant seemed to be tolerable in vivo. In a high TF–expressing gastric cancer xenograft model, 211At‐anti‐TF mAb in 1.2% SA exerted a significantly greater antitumor effect than nonprotected 211At‐anti‐TF mAb. Moreover, the antitumor activities of the protected immunoconjugate in gastric cancer xenograft models were dependent on the level of TF in cancer cells. These findings suggest the clinical availability of the radioprotectant and applicability of clone 1084 to 211At‐radioimmunotherapy., Although the astatinated anti–tissue factor (TF) monoclonal antibody (mAb) was disrupted by an astatine‐211–induced radiochemical reaction, we demonstrated that the immunoconjugates eluted in 0.6 or 1.2% sodium ascorbate (SA) solution were protected from antibody denaturation, which contributed to maintaining their cellular binding and antitumor activities. In gastric cancer xenograft models, astatine‐211–conjugated anti‐TF mAb protected by 1.2% SA exerted a potent antitumor effect dependent on TF expression on the cell membrane.

Diseases of immunity, including autoimmune diseases such as multiple sclerosis, transplantation graft rejection, allergy, and asthma, are prevalent and increasing in prevalence. They contribute to significant morbidity and mortality; however, few if any curative therapies exist, and those that are available lack either potency or specificity. Dendritic cells (DCs) are sentinels of the immune system that connect the innate and adaptive immune system and are critical regulators of both immunity and tolerance. We posited that the tolerogenic potential of DC could be harnessed to develop more specific and potent therapies for diseases of immunity by delivering autoantigen to a sufficient number of tolerogenic DCs in situ that could then inhibit pathogenic effector T cell responses. Specifically, we hypothesized that the steroid dexamethasone covalently coupled to a peptide antigen could be processed by DCs, induce tolerogenic DCs, and attenuate antigen-specific pathogenic T cell responses. To test this hypothesis, we synthesized a series of dexamethasone-peptide immunoconjugates by standard solid-phase peptide synthesis. The antigenic portion of the immunoconjugate could be presented by DCs, and the immunoconjugate induced a tolerogenic phenotype in DCs that then inhibited antigen-specific T cell proliferation in vitro. When the immunoconjugate was administered prophylactically in the murine experimental autoimmune encephalomyelitis model of multiple sclerosis, disease was attenuated compared to dexamethasone and peptide delivered as uncoupled components. Together, this work demonstrates the utility of immunoconjugates for inducing tolerance while establishing the foundation for future studies exploring methods to enrich and target DCs for tolerogenic therapies.

Mouse monoclonal antibodies to Hsp90β (β isoform of heat shock protein 90) have been shown to bind specifically to Hsp90β localized on the surface of tumor and nontransformed cells. After binding to the membrane-associated Hsp90β, the antibodies actively dissociated into the culture medium and were also internalized by the cells. An immunoconjugate based on the Hsp90β-specific antibody and the cytotoxic agent mertansine did not have high cytotoxic activity for tumor cells in vitro. Administration of Hsp90β-specific antibodies in mice did not affect the growth of the primary Lewis lung carcinoma, while tumor metastasis to the lungs decreased and the average lifespan of mice increased. The results indicate a certain therapeutic potential of antibodies to Hsp90β for the treatment of tumor diseases.

Over the past decade, theranostic imaging has emerged as a powerful clinical tool in oncology for identifying patients likely to respond to targeted therapies and for monitoring the response of patients to treatment. Herein, we report a theranostic approach to pretargeted radioimmunotherapy (PRIT) based on a pair of radioisotopes of copper: positron-emitting copper-64 (64Cu, t1/2 = 12.7 h) and beta particle-emitting copper-67 (67Cu, t1/2 = 61.8 h). This strategy is predicated on the in vivo ligation between a trans-cyclooctene (TCO)-bearing antibody and a tetrazine (Tz)-based radioligand via the rapid and bioorthogonal inverse electron-demand Diels–Alder reaction. Longitudinal therapy studies were conducted in a murine model of human colorectal carcinoma using an immunoconjugate of the huA33 antibody modified with TCO (huA33-TCO) and a 67Cu-labeled Tz radioligand ([67Cu]Cu-MeCOSar-Tz). The injection of huA33-TCO followed 72 h later by the administration of 18.5, 37.0, or 55.5 MBq of [67Cu]Cu-MeCOSar-Tz produced a dose-dependent therapeutic response, with the median survival time increasing from 68 d for the lowest dose to >200 d for the highest. Furthermore, we observed that mice that received the highest dose of [67Cu]Cu-MeCOSar-Tz in a fractionated manner exhibited improved hematological values without sacrificing therapeutic efficacy. Dual radionuclide experiments in which a single administration of huA33-TCO was followed by separate injections of [64Cu]Cu-MeCOSar-Tz and [67Cu]Cu-MeCOSar-Tz revealed that the positron emission tomography images produced by the former accurately predicted the efficacy of the latter. In these experiments, a correlation was observed between the tumoral uptake of [64Cu]Cu-MeCOSar-Tz and the subsequent therapeutic response to [67Cu]Cu-MeCOSar-Tz.

The primary treatment for malignant tumors remains to be resection. The strongest predictor of recurrence and postoperative prognosis is whether diseased tissue/cells remain(s) at the surgical margin. Cancer surgery entails surgeons having the capability to visually distinguish between subtle shades of color in attempts of differentiating between diseased tissue and healthy tissue under standard white-light illumination, as such tissue states appear identical at the meso-/macroscopic level. Accordingly, enhancing the capability of surgeons to do so such that they can accurately delineate the tumor margin is of paramount importance. Fluorescence-guided surgery facilitates in enhancing such capability by color-coding the surgical field with overlaid contrasting pseudo-colors from real-time intraoperative fluorescence emission via utilizing fluorescent constructs in tandem. Constructs undergoing clinical trials or that are FDA-approved provide peak fluorescence emission in the visible (405 – 700 nm) or near-infrared-I (NIR-I) spectral region (700–900 nm), whereby differentiation between tissue states progressively improves in sync with using constructs that emit longer wavelengths of light. Here, we repurpose the usage of such fluorescent constructs by establishing feasibility of a tumor-targeting immunoconjugate (cetuximab-IRDye800) having peak fluorescence emission at the NIR-I spectral region to provide improved tumor margin delineation by affording higher tumor-to-background ratios (TBRs) when measuring its off-peak fluorescence emission at the near-infrared-II (NIR-II) spectral region (1000–1700 nm) in in vivo applications. We prepared murine tumor models, administered such immunoconjugate, and imaged such models pre-/post-administration via utilizing imaging systems that separately afforded acquisition of fluorescence emission in the NIR-I or NIR-II spectral region. On doing so, we determined in vivo TBRs, ex vivo TBRs with/-out skin, and ex vivo biodistribution, all via measuring the fluorescence emission of the immunoconjugate at tumor site(s) at both spectral regions. Collectively, we established feasibility of using the immunoconjugate to afford improved tumor margin delineation by providing 2-fold higher TBRs via utilizing the NIR-II spectral region to capture off-peak fluorescence emission from a fluorescent construct having NIR-I peak fluorescence emission.

Triple-negative breast cancer (TNBC), representing ~15% of globally diagnosed breast cancer, is typically an incurable malignancy due to the lack of targetable surface targets for development of effective therapy. To address the unmet need for TNBC treatment, we recently determined that tissue factor (TF) is a useful surface target in 50–85% of patients with TNBC and developed a second-generation TF-targeting antibody-like immunoconjugate (called L-ICON) for preclinical treatment of TNBC. Using the chimeric antigen receptor (CAR) approach, here we develop and test TF-targeting CAR-engineered natural killer (TF-CAR-NK) cells that co-express CD16, the Fc receptor (FcγIII) to mediate antibody-dependent cellular toxicity (ADCC), for a preclinical assessment of immunotherapy of TNBC using TF-CAR-NK cell as single agent therapy and in combination with L-ICON. Our preclinical results demonstrate that TF-CAR-NK cells alone could kill TNBC cells and its efficacy was enhanced with L-ICON ADCC in vitro. Moreover, TF-CAR-NK cells were effective in vivo for the treatment of TNBC in cell line- and patient’s tumor-derived xenograft mouse models. Thus, this study established the proof of concept of targeting TF as a new target in CAR-NK immunotherapy for effective treatment of TNBC and may warrant further preclinical study and potentially future investigation in TNBC patients.

Brightly fluorescent semiconducting polymer dots (Pdots) are emerging as very useful probes for bioanalysis and imaging. Unfortunately, Pdot materials often suffer from limitations such as poor colloidal and physical stability, nonspecific adsorption, and relatively few reported surface chemistries and bioconjugate chemistries. To help address these limitations, we have developed dextran-functionalized Pdots (Dex-Pdots). This functionalization improves particle stability over a range of pH and at high ionic strength, hinders surface-induced unfolding, and enables the preparation of immunoconjugates via tetrameric antibody complexes (TAC). The utility of TAC-conjugated Dex-Pdots is demonstrated through a proof-of-concept fluorescence-linked immunosorbent assay (FLISA) for human erythropoietin (EPO), and through immunolabeling of human epidermal growth factor receptor 2 (HER2)-positive SK-BR3 breast cancer cells. The conjugates exhibited less nonspecific binding and greater specific binding than Pdots without dextran functionalization. Overall, dextran functionalization is a highly promising surface chemistry for biological applications of Pdots.

Not available

According to a 2020 World Health Organization report (Globocan 2020), cancer was a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. The aim of anticancer therapy is to specifically inhibit the growth of cancer cells while sparing normal dividing cells. Conventional chemotherapy, radiotherapy and surgical treatments have often been plagued by the frequency and severity of side effects as well as severe patient discomfort. Cancer targeting by drug delivery systems, owing to their selective targeting, efficacy, biocompatibility and high drug payload, provides an attractive alternative treatment; however, there are technical, therapeutic, manufacturing and clinical barriers that limit their use. This article provides a brief review of the challenges of conventional anticancer therapies and anticancer drug targeting with a special focus on liposomal drug delivery systems.

Sarcomas are one of the most difficult type of cancer to manage and treat because of their extremely heterogeneous molecular and morphological features. Despite the progress made over the years in the establishment of standard protocols for high and low grading/staging sarcoma patients, mostly with chemotherapy and/or radiotherapy, 50% of treated patients experience relapse episodes. Because of this, in the last 20 years, new therapeutic approaches for sarcoma treatment have been evaluated in preclinical and clinical studies. Among them, antibody-based therapies have been the most studied. Immunoconjugates consist of a carrier portion, frequently represented by an antibody, linked to a toxic moiety, i.e., a drug, toxin, or radionuclide. While the efficacy of immunoconjugates is well demonstrated in the therapy of hematological tumors and more recently also of epithelial ones, their potential as therapeutic agents against sarcomas is still not completely explored. In this paper, we summarize the results obtained with immunoconjugates targeting sarcoma surface antigens, considering both preclinical and clinical studies. To date, the encouraging results obtained in preclinical studies allowed nine immunoconjugates to enter clinical trials, demonstrating the validity of immunotherapy as a promising pharmacological tool also for sarcoma therapy.

Current interest in at-home diagnostic devices derives from their potential to disrupt expensive and time-consuming hospital-based diagnostic practices. Conventional immunoassays are often touted for use in at-home diagnostic devices, although in practice they are slow, labor-intensive and require expensive equipment. Here, we introduce bead-based sensors as alternative biomarker detection platforms for at-home diagnostic devices. The immunocomplex entrapment assay (ICEA), and the related enzyme-linked ICEA (ELICEA) offer enhancements over conventional immunoassays in terms of their speed, and minimal requirements for user intervention and instrumentation. In particular, we designed bead-based sensors to entrap large molecular weight complexes between target molecules and signal-generating immunoconjugates while allowing any unbound conjugates to escape from the bead. Confocal fluorescence microscopy was used to demonstrate the sensitivity, robustness, and reproducibility of the ICEA and ELICEA platforms. For example, we showed the intensity of signals generated by entrapped immunoconjugate complexes correlate linearly with the concentration of target molecule in the sample. We employed ICEA, and ELICEA platforms to detect human forms of immunoglobulins, albumin, and κ light chain (KLC). For example, we used ICEA to detect KLC at 5 μg·mL-1 in urine, which would allow for earlier diagnosis of Bence-Jones disease compared to conventional assays. In addition, we showed bead-entrapped phosphatases (AP) in immunocomplexes generate insoluble, blue-colored dyes from AP-substrates that accumulate in beads and allow for visual and cellphone camera-based detection of IgG to 10 ng·mL-1 within 20 min. Finally, we described ICEA and ELICEA platforms to analyze multiple target proteins within individual beads.

Key Clinical Message BI‐ALCL is a rare CD30+ T‐cell malignancy, which is known to complicate textured breast implants. The CD30‐targeting immunoconjugate, brentuximab vedotin, has been suggested for invasive BI‐ALCL; however, its efficacy for unresectable BI‐ALCL has not been demonstrated. We present a case of unresectable BI‐ALCL, which was successfully treated with brentuximab vedotin.

Pretargeted radioimmunotherapy (PRIT) based on the inverse electron demand Diels–Alder reaction has shown promise in murine models of disease, yet the radiation dosimetry of this approach must be optimized to make it a viable clinical option. To this end, we have leveraged two recent developments in pretargeted imaging—dendritic scaffolds and masking agents—to improve the dosimetric profile of a proof-of-concept PRIT system that is based on the huA33 antibody, a 177Lu-labeled tetrazine radioligand ([177Lu]Lu-DOTA-PEG7-Tz), and a mouse model of A33 antigen-expressing colorectal carcinoma. Pretargeting using an huA33 immunoconjugate bearing a trans-cyclooctene-decorated dendritic scaffold (sshuA33-DEN-TCO) produced significantly higher tumoral activity concentrations at 120 h post-injection (23.0 ± 2.2 %ID/g) than those achieved with an analogous, dendrimer-lacking immunoconjugate (12.7 ± 2.6 %ID/g). However, pretargeting using sshuA33-DEN-TCO also resulted in increased activity concentrations in the blood ...

Purpose: Interest in targeted alpha-therapy has surged due to α-particles' high cytotoxicity. However, the widespread clinical use of this approach could be limited by on-/off-target toxicities. Here, we investigated the inverse electron-demand Diels–Alder ligation between an 225Ac-labeled tetrazine radioligand and a trans-cyclooctene–bearing anti-CA19.9 antibody (5B1) for pretargeted α-radioimmunotherapy (PRIT) of pancreatic ductal adenocarcinoma (PDAC). This alternative strategy is expected to reduce nonspecific toxicities as compared with conventional radioimmunotherapy (RIT). Experimental Design: A side-by-side comparison of 225Ac-PRIT and conventional RIT using a directly 225Ac-radiolabeled immunoconjugate evaluates the therapeutic efficacy and toxicity of both methodologies in PDAC murine models. Results: A comparative biodistribution study of the PRIT versus RIT methodology underscored the improved pharmacokinetic properties (e.g., prolonged tumor uptake and increased tumor-to-tissue ratios) of the PRIT approach. Cerenkov imaging coupled to PRIT confirmed the in vivo biodistribution of 225Ac-radioimmunoconjugate but—importantly—further allowed for the ex vivo monitoring of 225Ac's radioactive daughters' redistribution. Human dosimetry was extrapolated from the mouse biodistribution and confirms the clinical translatability of 225Ac-PRIT. Furthermore, longitudinal therapy studies performed in subcutaneous and orthotopic PDAC models confirm the therapeutic efficacy of 225Ac-PRIT with the observation of prolonged median survival compared with control cohorts. Finally, a comparison with conventional RIT highlighted the potential of 225Ac-PRIT to reduce hematotoxicity while maintaining therapeutic effectiveness. Conclusions: The ability of 225Ac-PRIT to deliver a radiotherapeutic payload while simultaneously reducing the off-target toxicity normally associated with RIT suggests that the clinical translation of this approach will have a profound impact on PDAC therapy.

Heroin is a highly abused opioid that has reached epidemic status within the United States. Yet, existing therapies to treat addiction are inadequate and frequently result into rates of high recidivism. Vaccination against heroin offers a promising alternative therapeutic option but requires further development to enhance the vaccine’s performance. Hsp70 is a conserved protein with known immunomodulatory properties and is considered an excellent immunodominant antigen. Within an antidrug vaccine context, we envisioned Hsp70 as a potential dual carrier-adjuvant, wherein immunogenicity would be increased by co-localization of adjuvant and antigenic drug hapten. Recombinant Mycobacterium tuberculosis Hsp70 was appended with heroin haptens and the resulting immunoconjugate granted anti-heroin antibody production and blunted heroin-induced antinociception. Moreover, Hsp70 as a carrier protein surpassed our benchmark Her-KLH cocktail through antibody-mediated blockade of 6-acetylmorphine, the main mediator of heroin’s psychoactivity. The work presents a new avenue for exploration in the use of hapten-Hsp70 conjugates to elicit anti-drug immune responses.

α-Emission radiotherapeutics has potential to be one of most effective cancer therapeutics. Herein, we report a facile synthesis of an 211At-labeled immunoconjugate for use as an α-emission molecular targeting therapy. We synthesized a tetrazine probe modified with closo-decaborate(2-), a prosthetic group that forms a bioavailable stable complex with 211At. Our one-pot three-component double-click labeling method was used to attach decaborate to trastuzumab (anti-HER2 antibody) using decaborate-tetrazine and TCO-aldehyde probes without reducing the antibody binding affinity. Labeling the decaborate-attached trastuzumab with 211At produced in the cyclotron at the RIKEN Nishina Center, at which highly radioactive 211At can be produced, readily furnished the 211At-labeled trastuzumab with a maximum specific activity of 15 MBq μg−1 and retention of the native binding affinity. Intratumor injection of the 211At-labeled trastuzumab in BALB/c nude mice implanted with HER2-expressing epidermoid cancer cells yielded efficient accumulation at the targeted tumor site as well as effective suppression of tumor growth.