Bispecific Antibody Research Articles

Bispecific antibodies targeting BCMA or GPRC5D are highly effective in relapsed myeloma after CAR T-cell therapy

Despite the astonishing outcomes after chimeric antigen receptor (CAR) T-cell therapy for relapsed refractory multiple myeloma (RRMM), most patients eventually relapse. There are only limited data available on salvage therapies following relapse after BCMA-directed CAR T-cell therapy. Here, we analyzed outcomes of post-CAR T-cell therapy relapse and impact of different salvage strategies in an international cohort of 139 patients (n = 130 ide-cel, n = 9 cilta-cel), receiving talquetamab (n = 28), teclistamab (n = 37), combinations of immunomodulating drugs (IMiDs), proteasome inhibitors (PIs) or CD38 monoclonal antibodies (n = 43), and others (n = 31). The median time to relapse after CAR T-cell therapy was 5 months, 53% had the extramedullary disease (EMD) at relapse, associated with dismal post-relapse outcome (P = 0.005). Overall response and complete response upon salvage therapies were 79% and 39% for talquetamab, 64% and 32% for teclistamab, 30% and 0% for IMiDs/PIs/CD38, and 26% and 3% for others (P < 0.001). Duration of response, as well as median survival, was significantly improved with bispecific antibodies (P < 0.001, respectively). Bispecific antibodies seemed to overcome the poor prognosis associated with early relapse and EMD, and were independent predictors for improved survival in multivariable analysis. In summary, these results suggest bispecific antibodies as the standard of care for relapse after CAR T-cell therapy for RRMM.

The first-in-class bispecific antibody IBI318 (LY3434172) targeting PD-1 and PD-L1 in patients with advanced tumors: a phase Ia/Ib study

BackgroundThere is an unmet clinical need to enhance the response rate and safety of anti-PD-1/PD-L1-based cancer immunotherapy (IO). Herein, we presented the clinical study of IBI318 (LY3434172), a first-in-class bispecific antibody (bsAb) targeting PD-1 and PD-L1, in patients with advanced tumors.MethodsIn this open-label, multicenter Phase Ia/Ib study of IBI318, the Phase Ia involved dose escalation and a safety dose expansion, while the Phase Ib focused on preliminary safety and efficacy evaluation in non-small cell lung cancer (NSCLC) and nasopharyngeal carcinoma (NPC). In Phase Ia, patients with advanced tumors received IBI318 doses ranging from 0.3 to 1200 mg every two weeks (Q2W) to determine the recommended Phase 2 dose (RP2D). In Phase Ib, NSCLC or NPC patients from five cohorts with varying treatment histories received IBI318 at the RP2D. The primary endpoint was safety and the secondary endpoints included efficacy assessed by investigators according to RECIST v1.1, pharmacokinetics, immunogenicity, and pharmacodynamics.ResultsFrom February 11, 2019, to January 25, 2022, a total of 103 eligible patients were enrolled (Phase Ia, n = 55; Phase Ib, n = 48). The median follow-up was 10.1 months (range 0.7–28.6). The RP2D was determined to be 300 mg Q2W. Treatment-related adverse events (TRAEs) of any grades occurred in 88 patients (85.4%), while 10 patients (9.7%) experienced grade ≥ 3 TRAEs. The objective response rate (ORR) was 15.5% and the disease control rate (DCR) was 49.5% in all patients. In Phase Ib, the confirmed ORR was 45.5% in treatment-naïve NSCLC patients and 30.0% in IO-naïve NPC patients who had failed or were intolerant to platinum-based treatments.ConclusionsIBI318 demonstrated a favorable safety profile and preliminary efficacy in treatment-naïve NSCLC and IO-naïve NPC patients. Further clinical studies are needed to assess the full therapeutic potential of PD-1/PD-L1 dual inhibition with bsAbs.

The changing treatment landscape of EGFR-mutant non-small-cell lung cancer.

The discovery of the association between EGFR mutations and the efficacy of EGFR tyrosine-kinase inhibitors (TKIs) has revolutionized the treatment paradigm for patients with non-small-cell lung cancer (NSCLC). Currently, third-generation EGFR TKIs, which are often characterized by potent central nervous system penetrance, are the standard-of-care first-line treatment for advanced-stage EGFR-mutant NSCLC. Rational combinations of third-generation EGFR TKIs with anti-angiogenic drugs, chemotherapy, the EGFR-MET bispecific antibody amivantamab or local tumour ablation are being investigated as strategies to delay drug resistance and increase clinical benefit. Furthermore, EGFR TKIs are being evaluated in patients with early stage or locally advanced EGFR-mutant NSCLC, with the ambitious aim of achieving cancer cure. Despite the inevitable challenge of acquired resistance, emerging treatments such as new TKIs, antibody-drug conjugates, new immunotherapeutic approaches and targeted protein degraders have shown considerable promise in patients with progression of EGFR-mutant NSCLC on or after treatment with EGFR TKIs. In this Review, we describe the current first-line treatment options for EGFR-mutant NSCLC, provide an overview of the mechanisms of acquired resistance to third-generation EGFR TKIs and explore novel promising treatment strategies. We also highlight potential avenues for future research that are aimed at improving the survival outcomes of patients with this disease.

Anti-BCMA and GPRC5D bispecific antibodies in relapsed/refractory primary plasma cell leukemia: a case report

Anti-BCMA and GPRC5D bispecific antibodies in relapsed/refractory primary plasma cell leukemia: a case report

Polymeric Multivalent Fc Binding Peptides-Fabricated Clinical Compounding Bispecific Antibody Potentiates Dual Immunotherapy Targeting PD1 and CTLA-4.

Dual Opdivo plus Yervoy immunotherapy, targeting the immune checkpoints PD1 and CTLA-4, is successful in clinical use. However, it is associated with a high incidence of adverse events, and its therapeutic efficacy needs improving. In this study, polymeric multivalent Fc-binding peptides (PLG-Fc-III-4C) are employed to fabricate a bispecific antibody (PD1/CTLA-4 BsAb) to potentiate dual immunotherapy targeting PD1 and CTLA-4. The PD1/CTLA-4 BsAb is prepared by mixing PLG-Fc-III-4C with aPD1 and aCTLA-4 in an aqueous solution for 3 h using the clinically optimal 3:1 proportion of aPD1 to aCTLA-4. PD1/CTLA-4 BsAb significantly inhibits tumors in MC38 colon cancer-bearing mice more effectively than the combination of aPD1 and aCTLA-4, with tumor suppression rates of 96.8% and 77.3%, respectively. It also induces a higher percentage of CD8+ T cells and increases the secretion of effector cytokines while reducing Treg levels in tumors compared to phosphate-buffered saline, indicating significant tumor immunity regulation. Mechanistically, a 6.3-fold increase in PD1/CTLA-4 BsAb accumulation in tumors due to the tumor targeting ability of aPD1, and the PD1/CTLA-4 BsAb significantly reduces the adverse colitis event in healthy mice, compared to aPD1 and aCTLA-4. Thus, these findings provide a novel approach to enhance antitumor therapy using aPD1 and aCTLA-4.

A fully humanized von Willebrand disease type 1 mouse model as unique platform to investigate novel therapeutic options.

Patients suffering from von Willebrand disease (VWD) have reduced quality-of-life despite current treatment options. Moreover, innovation in VWD therapeutic strategies has essentially stalled and available treatments have remained unchanged for decades. Therefore, there is an unmet need to develop new therapeutic strategies for VWD-patients, especially for the large portion of those with VWD-type 1. Due to species differences, the available VWD murine models are not suitable for preclinical studies, making it difficult to test new therapeutic approaches in vivo. With this in mind, we generated mice selectively expressing human von Willebrand factor (VWF) and human GPIbα. Because this fully humanized model was found to express low VWF (12%) and FVIII (40%) levels with normal multimer profile and activity/antigen ratio, we repositioned it as a VWD-type 1 model (hVWD1 mice). In depth characterization of this model confirmed VWD-type 1 features with a decrease in platelet adhesion and thrombus formation in vitro. In vivo, a moderate bleeding phenotype was observed which was corrected upon the administration of recombinant-VWF or upon histamine-induced release of endothelial VWF. In search for new therapeutic options for VWD, we designed a bispecific single-domain antibody that bridges VWF to albumin (KB-V13A12). Remarkably, a single subcutaneous administration of KB-V13A12 coincided with a sustained 2-fold increase in VWF antigen levels for up to 10 days and normalized haemostasis in a tail-clip model in hVWD1 mice. We have developed a unique humanized mouse model for VWD-type 1 and a promising new therapeutic that corrected haemostasis in these mice.

A Phase 1/2 study of teclistamab, a humanized BCMA × CD3 bispecific Ab in Japanese patients with relapsed/refractory MM.

We characterized the safety and efficacy of the bispecific antibody teclistamab in Japanese patients with relapsed/refractory multiple myeloma (RRMM). Patients were pretreated with a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 monoclonal antibody (mAb). The primary endpoint was frequency and type of treatment-emergent adverse events (TEAEs) in phase 1, and overall response rate (ORR; ≥ partial response [PR]) in phase 2. In phase 1, 14 patients received once-weekly (QW) subcutaneous teclistamab (0.72mg/kg [n = 5]; 1.5mg/kg [n = 5]; 3mg/kg [n = 4]). No dose-limiting toxicities were observed. As of April 2024, 26 phase-2 patients received the recommended phase-2 dose (QW) (RP2D: 1.5mg/kg) of teclistamab. Biweekly (Q2W) dosing was allowed after maintaining response for ≥ 6months. At a median follow-up of 14.32months, ORR was 76.9% (≥ very good PR: 76.9%; ≥ complete response: 65.4%). Median duration of response, progression-free survival, and overall survival were not reached. Common TEAEs included CRS (grade ≤ 2), neutropenia, and infections. No patient had immune effector cell-associated neurotoxicity syndrome (ICANS) and dose reductions. Teclistamab demonstrated deep and durable responses in Japanese patients with RRMM, consistent with the global pivotal MajesTEC-1 study, supporting the potential for a new standard of care for Japanese RRMM patients.

Talquetamab in Multiple Myeloma: Efficacy, Safety, and Future Directions.

Relapsed and refractory multiple myeloma (RRMM) remains a challenging condition despite advances in immunotherapies. Novel bispecific antibodies (BsAbs), including talquetamab, have shown promising efficacy in heavily pretreated patients, even those with triple- and penta-refractory disease. Talquetamab, recently approved by the FDA and EMA, is indicated for patients who have progressed after at least three or four prior lines of therapy (LOTs). Administered following a step-up dosing phase to manage cytokine release syndrome (CRS), talquetamab demonstrated a high overall response rate (ORR) of approximately 70%, including in patients previously treated with T-cell redirecting therapies. Its safety profile is consistent with other BsAbs, with hematologic adverse events such as anemia and neutropenia commonly reported, alongside unique on-target off-tumor toxicities like dysgeusia and skin-related events. Infections were less frequent compared to other BsAbs. The optimal sequencing of talquetamab and other therapies, including CAR-T cell treatments, remains an area of active research, as resistance to anti-BCMA therapies presents ongoing clinical challenges. Current trials are exploring the use of talquetamab in combination therapies, as well as therapeutic strategies post-treating progression. The real-world data further support talquetamab's efficacy, making it a valuable addition to the RRMM treatment landscape.

Development and Characterization of a Lysosome-Targeting SLC3A2/PD-L1 Bispecific Antibody-Drug Conjugate for Enhanced Anti-Tumor Efficacy in Solid Tumors.

Bispecific antibodies (BsAbs) and antibody-drug conjugates (ADCs) have shown significant promise in cancer treatment, enhancing drug selectivity and therapeutic efficacy as demonstrated in multiple clinical studies. Bispecific antibody-drug conjugates (BsADCs), which combine the targeting capabilities of BsAbs with the cytotoxic potential of ADCs, offer a novel approach to overcoming several challenges associated with ADCs, including limited internalization, off-target toxicity, and drug resistance. In this study, we identified solute carrier family 3 member 2 (SLC3A2) as a highly expressed protein in a variety of solid tumors, making it a promising therapeutic target. We developed a bispecific antibody targeting SLC3A2 and PD-L1, and conjugated it to monomethyl auristatin E (MMAE) to create the SLC3A2/PD-L1 BsADC. The SLC3A2/PD-L1 BsAb effectively blocked PD-1 binding to PD-L1 and activated T cells, while also facilitating lysosomal targeting and degradation of poorly internalized PD-L1 antibodies. The SLC3A2/PD-L1 BsADC demonstrated superior anti-tumor efficacy in PD-L1 low-expressing tumor cells compared to single-target ADCs in both in vitro studies and in multiple xenograft and immunocompetent mouse models. Overall, our engineered SLC3A2/PD-L1 BsADC exhibited enhanced internalization and improved tumor cell targeting, highlighting the potential of lysosome-targeting BsAbs in advancing ADC therapeutic strategies for solid tumors.

Preparing Nurses for CD20-CD3 Bispecific Antibody Treatment in Patients With Non-Hodgkin Lymphoma: A Scoping Review of Adverse Events and Management Strategies From Early Phase and Pivotal Trials.

Bispecific T-cell engaging antibodies (BsAbs) are novel agents used to treat B-cell non-Hodgkin lymphoma (B-NHL); these agents demonstrate a different toxicity profile compared with standard chemoimmunotherapy. To describe common adverse events (AEs) experienced by patients with B-NHL during BsAb treatment. MEDLINE, EMCARE, and EMBASE were searched for relevant studies. Prospective interventional clinical trials of CD20-CD3 BsAbs in late development reporting on safety data for B-NHL patients, published until March 2023, were included. This search identified 1481 records; 28 met the inclusion criteria. Cytokine release syndrome (CRS), neutropenia, pyrexia, and anemia were the most commonly reported AEs. CRS primarily occurred during the first cycle of treatment and was mostly low grade; 14 publications (48%) reported a grade ≥3; however, these occurred in less than 10% of patients. Mitigation strategies included premedication with corticosteroids, antipyretics, and antihistamines; step-up dosing; and planned hospitalizations. Two articles reported common signs and symptoms of CRS, which included pyrexia (98% and 99%), chills (13% and 35%), tachycardia (27% and 28%), and hypotension (24% and 38%). Supportive management, tocilizumab, and corticosteroids were widely used (reported in 16/28 studies) for the treatment of CRS. Patient risk factors for CRS included high tumor burden, bone marrow infiltration, and circulating disease. The AE profile of BsAbs requires specialized nurses, skilled in assessing patients for risk factors and recognizing signs and symptoms of AEs. Findings from this review will contribute to cancer nurses' knowledge of CD20-CD3 BsAbs for B-NHL, optimizing the quality and safety of patient care.

Interleukin-17A is a potential therapeutic target predicted by proteomics for systemic sclerosis patients at high risk of pulmonary arterial hypertension

We explored effective therapeutic targets for systemic sclerosis (SSc) patients with high risk for pulmonary arterial hypertension (PAH) by plasma proteomics analysis. A total of fifty-seven patients with SSc were enrolled in the study and the prevalence of PAH was 19.3%. On the other hand, 75.4% of SSc patients showed the ratio of forced vital capacity percentage/diffusing capacity of the lungs for carbon monoxide percentage> 1.6 and met criteria for high risk of PAH. Identification of elevated plasma proteins in SSc patients with high risk of PAH, followed by upstream regulator analysis, predicted interleukin (IL)-17A as a major upstream molecule. Furthermore, we performed in vitro neutralization study using MT-6194, a bispecific antibody targeting both IL-17A and IL-6 receptor. We found that MT-6194 broadly suppressed the increased expression of downstream molecules of IL-17A including IL-17A-related cytokines/chemokines, IL-17A-driven NF\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\kappa$$\\end{document}B pathway and IL-6-driven JAK/STAT pathway which were shown to be increased in SSc patients with high risk of PAH by the proteomics. Consequently, it is revealed that IL-17A is a promising target for early intervention in SSc patients with high risk for PAH.

Total (Immuno)Therapy: Version 2.0.

Among patients with poly-refractory myeloma, autologous chimeric antigen receptor T-cell therapy offers exceptional promise. With the availability of bispecific antibodies, a total immunotherapeutic strategy in combination with chimeric antigen receptor T-cell therapy is now feasible. See related article by Fandrei, p. XX.

A surprising complete response to cadonilimab in a primary metastatic cervical cancer: a case report

The outcome of patients with recurrent/metastatic cervical cancer (R/M CC) is poor, with a 5-year survival rate of only 10%–20%. Recent advances in immunotherapy renewed its interest in R/M CC treatment. It has been suggested that cadonilimab, a novel bispecific antibody targeting programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4), significantly improved the survival outcomes of the R/M CC. In the present study, we reported a programmed death ligand 1 (PD-L1) and human epidermal growth factor receptor 2 (HER-2) positive CC case at stage IV who was treated with cadonilimab and achieved a surprising radiographic complete response (CR) for 10 months, even in the PD-L1 negative metastatic site. Demographic, clinical, histopathological, laboratory, treatment regime and imaging data were recorded. Unfortunately, the patient progressed rapidly during maintenance therapy when cadonilimab was replaced by sintilimab, the monoclonal antibody against PD-1, indicating the more powerful anti-tumor activity of dual blockade immunotherapy. To conclude, cadonilimab offers a promising and effective therapeutic approach for R/M CC. Notably, HER-2 is also expected to be a new reference target for cadonilimab therapy.

Real‐world practitioner perceptions of CARTITUDE‐4 results for patients with previously treated multiple myeloma

AbstractIntroductionInitially approved for the fifth‐line or later therapeutic setting, the chimeric antigen receptor (CAR) T‐cell regimen ciltacabtagene autoleucel (cilta‐cel) was recently approved for second‐line (2L) treatment in relapsed/refractory multiple myeloma (RRMM). Oncology practitioners use clinical trials to inform treatment, but real‐world impressions and impact on practice are lacking. We aimed to determine whether presenting CARTITUDE‐4 clinical trial data would impact real‐world preferences/perceptions around CAR T‐cell therapy.MethodsRecruiting from the Cardinal Health Oncology Provider Extended Network (OPEN), we surveyed hematologists/oncologists to investigate fourth‐line (4L) preferences in a hypothetical patient with triple‐class–refractory MM. We posed the same questions and answers before and after the trial presentation and compared pre‐/post‐preferences toward cilta‐cel and sequencing relative to bispecific antibodies (BsAbs). Using the same methodology as described above, we also performed a secondary analysis comparing pre‐/post‐perceptions on the use of CAR T‐cell therapy in earlier lines for patients with triple‐class–refractory MM.ResultsAmong 50 respondents, decision‐making factors before the trial presentation included CAR T‐cell center availability (58%), comorbidities (52%), and center locations (34%). Additionally, 48% of 46 respondents chose 4L cilta‐cel. Among 47, 40% wanted more real‐world/long‐term CAR T‐cell therapy outcomes in any line, 38% wanted more 2L data, and 34% favored 2L/third‐line (3L) use. After the presentation, the preference for cilta‐cel doubled from 48% to 88% (p &lt; 0.001) among 50 respondents and rose from 34% to 55% (p = 0.001) for earlier‐line CAR T‐cell therapy among 49. Moreover, 55% of 49 respondents preferred CAR T‐cell therapy prior to BsAbs.DiscussionWe have shown that making oncology practitioners aware of trials precipitated decision‐making factors and led to notable, significant shifts in future intended practice patterns. Being aware of trial data enables practitioners to make more informed decisions, tailor therapies to individual patients, and ultimately improve outcomes.

Sequence and Configuration of a Novel Bispecific Antibody Format Impacts Its Production Using Chinese Hamster Ovary (CHO) Cells.

There are a number of new format antibody-inspired molecules with multiple antigen binding capabilities in development and clinical evaluation. Here, we describe the impact of the sequence and configuration of a unique bispecific antibody format (termed BYbe) using a panel of four BYbe's and the three IgG1s from which they were derived on their production in a Chinese hamster ovary (CHO) cell expression system. Following transfection and selection, one bispecific antibody format yielded fewer mini-pools in comparison to the other bispecific cell pools. When the top 12 expressing stable mini-pools of all BYbe configurations and sequences were evaluated, both the dsscFv sequence and antibody chain configuration or placement directly impacted productivity. The cell-specific productivity (qP, pg/cell/day) was lower in all BYbe cell pools compared to the IgG1 cell lines. However, when the actual molecules/cell/day produced were considered, three of the four bispecific cell pools outproduced the parental IgG1 cell pools. While gene copy number did not correlate to productivity, mRNA analysis showed that for specific BYbe formats there was a strong correlation with productivity. In summary, we describe how bispecific antibody format configuration impacts the cell line construction process and yield of product from CHO cells.

A novel designed anti-PD-L1/OX40 bispecific antibody augments both peripheral and tumor-associated immune responses for boosting anti-tumor immunity.

Bispecific antibodies (BsAbs) combining simultaneous PD-L1 blockade and conditional co-stimulatory receptor activation have been developed to improve immune checkpoint therapy response. However, several PD-L1-based BsAbs have encountered clinical challenges, including insufficient activity or unexpected toxicity. In this study, we propose OX40 as a more suitable target partner for PD-L1-based BsAb design compared to ongoing clinical partners (CD27 and 4-1BB). We present a novel Fc-silenced tetravalent PD-L1/OX40 BsAb (EMB-09), which efficiently blocks PD-1/PD-L1 interactions and induces PD-L1-dependent OX40 activation, leading to enhanced T cell activation. EMB-09 demonstrated improved anti-tumor activity compared to the anti-PD-L1 monoclonal antibody. Significantly, EMB-09 activated effector memory T cells in peripheral immune system, promoted the influx of stem-like CD8+ T cells into the tumor site, resulting in a more active phenotype of CD8+ tumor-infiltrating lymphocytes. In an ongoing first-in-human study in patients with advanced refractory solid tumors (NCT05263180), EMB-09 demonstrated a consistent pharmacodynamic response and early efficacy signals.

Current treatment approach and future perspectives in B cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) represent the two major subtypes of mature B cell lymphoma. A deeper understanding of tumor biology, as well as molecular classification characterized by targetable gene alterations, and the introduction of novel treatment options, including targeted drugs (e.g., antibody-drug conjugates and small molecules [e.g., Bruton tyrosine kinase inhibitor]) and immune therapies (e.g., chimeric antigen receptor [CAR] T cell therapy and bispecific antibody [BsAb]), has changed the treatment paradigms for DLBCL and FL. In clinical practice, however, treatment regimens are determined mainly based on prior treatment history, duration of response after previous treatment, patient age, and patient frailty because there have been few randomized trials to inform treatment selection for patients with relapsed or refractory disease and because there is no single prognostic index that guides suitable treatment for each patient. In this review, we summarize the treatment options for DLBCL and FL and discuss the treatment strategies for these two subtypes. We also discuss future perspectives for the treatment of these subtypes.

Discovery and preclinical evaluation of BPB-101: a novel triple functional bispecific antibody targeting GARP-TGF-β complex/SLC, free TGF-β and PD-L1.

In the tumor microenvironment (TME), the transforming growth factor-β (TGF-β) and programmed cell death receptor 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling axes are complementary, nonredundant immunosuppressive signaling pathways. Studies have revealed that active TGF-β is mainly released from the glycoprotein A repetitions predominant (GARP)-TGF-β complex on the surface of activated regulatory T cells (Tregs), B cells, natural killer (NK) cells, and tumor cells. The currently available antibodies or fusion proteins that target TGF-β are limited in their abilities to simultaneously block TGF-β release and neutralize active TGF-β in the TME, thus limiting their antitumor effects. We designed and constructed a bispecific, trifunctional antibody, namely, BPB-101, that specifically targets the GARP-TGF-β complex and/or small latent complex (SLC), active TGF-β, and PD-L1. The binding ability of BPB-101 to the different antigens was determined by ELISA, FACS, and biolayer interferometry (BLI). The blocking ability of BPB-101 to the TGF-β and PD-1/PD-L1 signaling axes was determined by reporter gene assay (RGA). The antitumor effect and biosafety of BPB-101 were determined in a transgenic mouse tumor model and cynomolgus monkeys, respectively. Stability assessments, including stability in serum, after exposure to light, after repeated freeze-thaw cycles, and after high-temperature stress tests had been completed to evaluate the stability of BPB-101. BPB-101 bound efficiently to different antigenic proteins: the GARP-TGF-β complex and/or SLC, active TGF-β, and PD-L1. Data showed that BPB-101 not only effectively inhibited the release of TGF-β from human Tregs, but also blocked both the TGF-β and PD-1/PD-L1 signaling pathways. In an MC38-hPD-L1 tumor-bearing C57BL/6-hGARP mouse model, BPB-101 at a dose of 5 mg/kg significantly inhibited tumor growth, with a complete elimination rate of 50%. Stability assessments confirmed the robustness of BPB-101. Furthermore, BPB-101 showed a favorable safety profile in nonhuman primate (NHP) toxicity studies. BPB-101 is a potentially promising therapeutic candidate that may address unmet clinical needs in cancer immunotherapy, thus, BPB-101 warrants further clinical investigation.

Odronextamab: First Approval.

Odronextamab (Ordspono™), a CD20xCD3 bispecific antibody, is being developed by Regeneron Pharmaceuticals for the treatment of B-cell non-Hodgkin's lymphoma. On 26 August 2024, odronextamab received its first approval in the EU as monotherapy for the treatment of adult patients with relapsed/refractory follicular lymphoma (FL) or relapsed/refractory diffuse large B-cell lymphoma (DLBCL) after ≥ 2lines of systemic therapy. Clinical trials in various other B-cell non-Hodgkin's lymphoma, including mantle cell lymphoma, marginal zone lymphoma and chronic lymphocytic leukaemia, are underway in multiple countries. This article summarizes the milestones in the development of odronextamab leading to this first approval for the treatment of adult patients with relapsed/refractory FL or relapsed/refractory DLBCL.

Generation of chimeric antigen receptor T cells targeting p95HER2 in solid tumors

The redirection of T lymphocytes against tumor-associated or tumor-specific antigens, using bispecific antibodies or chimeric antigen receptors (CAR), has shown therapeutic success against certain hematological malignancies. However, this strategy has not been effective against solid tumors. Here, we describe the development of CAR T cells targeting p95HER2, a tumor-specific antigen found in HER2-amplified solid tumors. These CAR T cells display robust activity against p95HER2-expressing cell lines but demonstrate limited efficacy against patient-derived xenografts. As p95HER2 is invariably detectable on tumor cells that overexpress HER2, but not those that express HER2 at normal levels, we arm p95HER2-specific CAR T cells with affinity-tuned bispecific antibodies against HER2 and CD3 in order to redirect them only to HER2-amplified cells. The combination of p95HER2.CAR T cells and HER2 x CD3 bispecific antibodies lead to a complete regression in three HER2-positive, patient-derived mouse xenografts tumor models. This combination represents a promising strategy to redirect T cells against a subset of HER2-positive tumors.