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Phase 3 trials Viale-A and Viale-C evaluated health-related quality of life (HRQoL) in patients with AML unfit for intensive chemotherapy who received venetoclax (VEN) + (AZA) (Viale-A) or low-dose cytarabine (LDAC) (Viale-C) or placebo (PBO) + AZA or LDAC. Patient-reported outcomes included: EORTC QLQ-C30 global health status (GHS/QoL) and physical functioning (PF), PROMIS Cancer Fatigue Short Form 7a (Fatigue), and EQ-5D-5L health status visual analog scale (HS-VAS). Time to deterioration (TTD), defined as worsening from baseline in meaningful change thresholds (MCT) of ≥10, 5, or 7 points for GHS/QoL or PF, fatigue, and HS-VAS, respectively, was assessed; differences between groups were analyzed using Kaplan-Meier and unadjusted log-rank analyses. VEN + AZA vs PBO + AZA patients had longer TTD in GHS/QoL (P = 0.066) and fatigue (P = 0.189), and significantly longer TTD in PF (P = 0.028) and HS-VAS (P < 0.001). VEN + LDAC vs PBO + LDAC patients had significantly longer TTD in GHS/QoL (P = 0.011), PF (P = 0.020), and fatigue (P = 0.004), and a trend in HS-VAS (P = 0.057). Approximately 43%, 35%, 32%, and 18% of patients treated with VEN + AZA, AZA + PBO, VEN + LDAC, or LDAC + PBO, respectively, saw improvements >MCT in GHS/QoL. Overall, VEN may positively impact HRQoL in patients with AML ineligible for intensive chemotherapy, leading to longer preservation of functioning and overall health status. © 2022, The Author(s).

Background: AU-007 is a computationally designed, monoclonal antibody that binds to IL-2 on its CD25 binding epitope. AU-007 bound IL-2 (A/IL-2) cannot bind to high affinity trimeric IL-2 receptors (IL-2R) consisting of CD25, CD122, and CD132 expressed on Tregs and vascular endothelium, but its binding to low affinity dimeric IL-2Rs (CD122 and CD132) expressed on T effector and NK cells is unhindered. Thus, AU-007 redirects endogenously produced or exogenous IL-2 (aldesleukin) towards activation of immune stimulating T effector and NK cells, while diminishing Treg activation and expansion. AU-007 will also bind and redirect newly secreted endogenous IL-2 resulting from A/IL-2 driven T cell expansion in the tumor, converting a Treg mediated autoinhibitory loop into an immune stimulating loop. AU-007 is unique in the IL-2 therapeutic field as engineered exogenous, recombinant "non-CD25" IL-2s in development cannot address the autoinhibitory effect of endogenous IL-2. Preclinically, AU-007 has been demonstrated to capture endogenous human IL-2 in vivo. AU-007 with a single low dose of IL-2 has demonstrated efficacy in multiple cancer models and has an excellent safety profile in non-human primates. Method(s): This first-in-human, multicenter, open label Phase 1- 2 study evaluates the safety, tolerability, and initial efficacy of AU-007 +/- aldesleukin in patients with advanced solid tumors (CT-2021-CTN-03938-1). Phase 1 consists of 3 escalation arms each starting with a single 1+2 escalation cohort followed by 3+3 escalation cohorts to define the recommended Phase 2 dose (RP2D) or maximum tolerated dose (MTD). Patients with melanoma, renal cell carcinoma (RCC) and 17 selected solid tumors are eligible. Prior treatment with check point inhibitors is allowed. In Arm A, escalating doses of Q2w AU-007 are evaluated in sequential escalation cohorts. In Arm B, a single dose of aldesleukin is given with the initial AU-007 dose. AU-007 is given at a fixed dose Q2w with an esca

Background: AU-007 is a computationally designed, monoclonal antibody that binds to IL-2 on its CD25 binding epitope. AU-007 bound IL-2 (A/IL-2) cannot bind to high affinity trimeric IL-2 receptors (IL-2R) consisting of CD25, CD122, and CD132 expressed on Tregs and vascular endothelium, but its binding to low affinity dimeric IL-2Rs (CD122 and CD132) expressed on T effector and NK cells is unhindered. Thus, AU-007 redirects endogenously produced or exogenous IL-2 (aldesleukin) towards activation of immune stimulating T effector and NK cells, while diminishing Treg activation and expansion. AU-007 will also bind and redirect newly secreted endogenous IL-2 resulting from A/IL-2 driven T cell expansion in the tumor, converting a Treg mediated autoinhibitory loop into an immune stimulating loop. AU-007 is unique in the IL-2 therapeutic field as engineered exogenous, recombinant "non-CD25" IL-2s in development cannot address the autoinhibitory effect of endogenous IL-2. Preclinically, AU-007 has been demonstrated to capture endogenous human IL-2 in vivo. AU-007 with a single low dose of IL-2 has demonstrated efficacy in multiple cancer models and has an excellent safety profile in non-human primates. Method(s): This first-in-human, multicenter, open label Phase 1- 2 study evaluates the safety, tolerability, and initial efficacy of AU-007 +/- aldesleukin in patients with advanced solid tumors (CT-2021-CTN-03938-1). Phase 1 consists of 3 escalation arms each starting with a single 1+2 escalation cohort followed by 3+3 escalation cohorts to define the recommended Phase 2 dose (RP2D) or maximum tolerated dose (MTD). Patients with melanoma, renal cell carcinoma (RCC) and 17 selected solid tumors are eligible. Prior treatment with check point inhibitors is allowed. In Arm A, escalating doses of Q2w AU-007 are evaluated in sequential escalation cohorts. In Arm B, a single dose of aldesleukin is given with the initial AU-007 dose. AU-007 is given at a fixed dose Q2w with an esca

Phase 3 trials Viale-A and Viale-C evaluated health-related quality of life (HRQoL) in patients with AML unfit for intensive chemotherapy who received venetoclax (VEN) + (AZA) (Viale-A) or low-dose cytarabine (LDAC) (Viale-C) or placebo (PBO) + AZA or LDAC. Patient-reported outcomes included: EORTC QLQ-C30 global health status (GHS/QoL) and physical functioning (PF), PROMIS Cancer Fatigue Short Form 7a (Fatigue), and EQ-5D-5L health status visual analog scale (HS-VAS). Time to deterioration (TTD), defined as worsening from baseline in meaningful change thresholds (MCT) of ≥10, 5, or 7 points for GHS/QoL or PF, fatigue, and HS-VAS, respectively, was assessed; differences between groups were analyzed using Kaplan-Meier and unadjusted log-rank analyses. VEN + AZA vs PBO + AZA patients had longer TTD in GHS/QoL (P = 0.066) and fatigue (P = 0.189), and significantly longer TTD in PF (P = 0.028) and HS-VAS (P < 0.001). VEN + LDAC vs PBO + LDAC patients had significantly longer TTD in GHS/QoL (P = 0.011), PF (P = 0.020), and fatigue (P = 0.004), and a trend in HS-VAS (P = 0.057). Approximately 43%, 35%, 32%, and 18% of patients treated with VEN + AZA, AZA + PBO, VEN + LDAC, or LDAC + PBO, respectively, saw improvements >MCT in GHS/QoL. Overall, VEN may positively impact HRQoL in patients with AML ineligible for intensive chemotherapy, leading to longer preservation of functioning and overall health status.

Most current analysis tools for antibody next-generation sequencing data work with primary sequence descriptors, leaving accompanying structural information unharnessed. We have used novel rapid methods to structurally characterize the complementary-determining regions (CDRs) of more than 180 million human and mouse B-cell receptor (BCR) repertoire sequences. These structurally annotated CDRs provide unprecedented insights into both the structural predetermination and dynamics of the adaptive immune response. We show that B-cell types can be distinguished based solely on these structural properties. Antigen-unexperienced BCR repertoires use the highest number and diversity of CDR structures and these patterns of naïve repertoire paratope usage are highly conserved across subjects. In contrast, more differentiated B-cells are more personalized in terms of CDR structure usage. Our results establish the CDR structure differences in BCR repertoires and have applications for many fields including immunodiagnostics, phage display library generation, and “humanness” assessment of BCR repertoires from transgenic animals. The software tool for structural annotation of BCR repertoires, SAAB+, is available at https://github.com/oxpig/saab_plus.

Every entirely sequenced genome reveals 100s to 1000s of protein sequences for which the only annotation available is 'hypothetical protein'. Thus, in the human genome and in the genomes of pathogenic agents there could be 1000s of potential, unexplored drug targets. Computational prediction of protein function can play a role in studying these targets. We shall review the challenges, research approaches and recently developed tools in the field of computational function-prediction and we will discuss the ways these issues can change the process of drug discovery.

Every entirely sequenced genome reveals 100s to 1000s of protein sequences for which the only annotation available is 'hypothetical protein'. Thus, in the human genome and in the genomes of pathogenic agents there could be 1000s of potential, unexplored drug targets. Computational prediction of protein function can play a role in studying these targets. We shall review the challenges, research approaches and recently developed tools in the field of computational function-prediction and we will discuss the ways these issues can change the process of drug discovery.