The presentation will review preclinical and translational strategies to help identify the optimal dose in the clinical setting. Examples of preclinical pharmacodynamic studies for CD3 bispecifics and immune agonist bispecific antibodies will be provided, as well as clinical biomarker data to monitor pharmacodynamic activity in the clinic.

ISB 2001, trispecific molecule based on the BEAT platform. ISB 2001 targets CD3 on T cells and co-targets BCMA and CD38 on Multiple Myeloma (MM) cells. Binding arms on ISB 2001 were derived from a synthetic phage display library using a common light chain. ISB 2001 exhibited higher killing potency (EC50) than all tested BCMA specific T cell engagers (TCE). In vivo tests with ISB 2001 show IgG-like half-life and efficient tumour eradication. Based on the specific dual targeting of MM cells, significant benefit is anticipated for relapsed/refractory patients, who may experience tumor escape through target downregulation mechanisms.

By associating a blocking anti-PD-L1 antibody arm with an agonist anti-CD28 antibody arm, we generated a PD-L1xCD28 bsAb (NI-3201) inducing CD28 signaling upon PD-L1 blockade on PD-L1+ tumor and immune cells (e.g., antigen-presenting cells). Data from the preclinical development of NI-3201 will be presented, with a focus on in vitro and in vivo de-risking activities.

All current therapeutic monoclonal antibodies are based on IgG. For the past 25 years, we have been working on IgA as a different isotype to treat cancer, since it activates neutrophils very efficiently, even the suppressive type of neutrophils in the TME. At the moment, we are developing a bispecific antibody based on IgA, that also blocks CD47 as a myeloid checkpoint inhibitor molecule.

T cell costimulation via CD28 signaling (Signal 2) enhances anti-tumor activity. However, solid tumors often lack CD28 ligands. We hypothesized that tumor-associated-antigen x CD28 bispecifics could focus a strong Signal 2 in the tumor microenvironment. We assessed antigens including CEACAM5, mesothelin, STEAP-1, and Trop-2. Such bispecifics enhanced T cell degranulation, cytokine secretion, and tumor-cell cytotoxicity only when coupled with TCR engagement (Signal 1). To promote a favorable therapeutic index, we also tuned bispecific formats and affinities to preferentially target cancer cells with high antigen expression. Costimulatory bispecifics against these four tumor antigens show promising activity and warrant further development for solid tumors.

CB307 is a novel trispecific Humabody therapeutic targeting CD137, prostate specific membrane antigen (PSMA) and human serum albumin (HSA), enabling tumour-specific T cell activation, with minimal systemic activation. It is generated by formatting fully human VH domains from the Crescendo Mouse. CB307 mediates CD137 reporter cell signaling in PSMA dependent manner and enhances human T cells activity in co-culture assay. The first human clinical study (NCT04839991) is ongoing.

Monoclonal antibodies that block the programmed cell death 1 (PD-1) checkpoint have revolutionized cancer immunotherapy. We have recently described a class of costimulatory bispecifics that crosslink a tumor specific antigen to CD28 (e.g. PSMAxCD28, REGN5678), synergize with the broader anti-PD-1 approach, and endow responsiveness against tumors that otherwise do not respond to anti-PD-1 alone: such as, metastatic castration-resistant prostate cancer (mCRPC). By combining these costimulatory bispecifics as off-the-shelf drugs, with Libtayo (aPD-1), we have the opportunity to create novel therapeutic synergies to address some of the most difficult-to-treat cancers.

Success of bispecific antibodies (bsAbs) in solid tumors is still limited due to (i) lack of accessibility of the tumor site for immune effector cells, (ii) lack of sufficiently tumor-specific target antigens and (iii) lack of costimulatory “signal 2” that enables thorough and long-lasting T cell activation. Using our proprietary antibody platform, we overcome these limitations by a combination of functionally interrelated bsAbs that target two different antigens on tumor cells, and notably also the tumor vasculature, and stimulate CD3 and CD28 on T cells.