Abstract 4556: Preclinical pharmacology and safety of RO7297089, a novel anti-BCMA/CD16a bispecific antibody for the treatment of multiple myeloma

Abstract

RO7297089 is a bispecific antibody (IgG-scFv) targeting Bcell maturation antigen (BCMA) and CD16a (FcγRIIIA) that is being developed for the treatment of multiple myeloma (MM). BCMA is exclusively expressed on plasmablasts and differentiated plasma cells (PCs), and is overexpressed on malignant PCs in MM patients. CD16a is expressed on natural killer (NK) cells, monocytes, mast cells, and macrophages. Herein, we characterized the mode of action and safety profile of RO7297089 in vitro and in vivo. RO7297089 showed potent cell killing when using BCMA+ MM tumor cell lines as target cells and human peripheral blood mononuclear cells, NK cells or macrophages as effector cells. Minimal increases in TNFα (2x) and IFNγ (4x), but not other cytokines/chemokines, were observed compared to the vehicle control treatment only in the presence of the BCMA+ MM tumor cell line up to the concentration tested. This suggests that, unlike T-cell engagers, the risk of cytokine release syndrome in patients receiving RO7297089 is low. Cynomolgus monkey is the only relevant nonclinical species for RO7297089 as it showed binding to both recombinant CD16 and BCMA with comparable affinity to human antigens. Following five weekly intravenous administrations to monkeys at 0, 15, and 50 mg/kg, RO7297089 was well tolerated. In line with the mechanism of action, there were no test article-related cytokine increases or adverse findings observed in both dose levels. Systemic exposure of RO7297089 was approximately dose proportional from 15 to 50 mg/kg. Anti-drug antibodies (ADA) were observed in some animals at both dose levels, and ADA-related decreases in concentrations were observed at only 15 mg/kg. To evaluate in vivo activity, RO7297089-related effects on total plasma sBCMA and PCs were assessed. Elevations of sBCMA levels (100x) were observed post dose at both dose levels, and these effects returned to predose levels in animals that did not maintain concentrations at 15 mg/kg, suggesting that RO7297089 bound to and stabilized circulating cynomolgus sBCMA. Time- and dose-dependent reductions in serum IgM levels were observed at both dose levels. Changes in PC numbers were not detected by immunophenotyping; however, gene expression analysis of PC markers was included and demonstrated clear reductions in mRNA expression levels of PC markers including BCMA and J-chain in blood at both dose levels, suggesting reductions in BCMA+ cells. Collectively, these studies suggest that RO7297089 selectively kills BCMA+ cells by engaging CD16a-positive immune cells and has a favorable safety profile. Citation Format: Satoko Kakiuchi-Kiyota, Melissa M. Schutten, Adeyemi O. Adedeji, Hao Cai, Robert Hendricks, Luna Liu, Sivan Cohen, Aaron M. Fullerton, Nicholas Corr, Lanlan Yu, Denise de Almeida Nagata, Shelly Zhong, Michael Dillon, Christoph Spiess, Steve R. Leong, Bing Zheng, Susanne Wingert, Uwe Reusch, Stefan Knackmuss, Thorsten Ross, Andrew Polson, Ayse M. Ovacik. Preclinical pharmacology and safety of RO7297089, a novel anti-BCMA/CD16a bispecific antibody for the treatment of multiple myeloma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4556.

The evolving status of immunotherapies in multiple myeloma: the future role of bispecific antibodies

“…Another option under development is BsAbs designed to activate endogenous NK cells. The BCMA‐CD16a‐directed BsABs AFM 26 and R07297089 have shown NK‐mediated MM cell lysis in vitro 176 and safety in an animal model of MM respectively 177 . Combining T cell and NK‐redirecting therapies could be a potent treatment option, although at the moment, no NK BsAbs are in clinical trials in MM.…”

Immunotherapy of Multiple Myeloma: Promise and Challenges

“… 106 , 185 Another is RO7297089 (AFM26), a bi-specific designed to engage myeloma cell BCMA and NK CD16A, which exhibited an acceptable safety profile in preclinical work. 186 An additional example is Compass Therapeutics’ bi-specific CTX-4419 in which the binding partners are myeloma cell BCMA and NK cell p30, demonstrating that although NK CD16A binding may enhance cytotoxicity, it may not be a requirement for anti-myeloma activity. Some promise has been shown in preclinical work on CTX-4419.…”

Nonclinical Pharmacokinetics, Pharmacodynamics, and Translational Model of RO7297089, A Novel Anti-BCMA/CD16A Bispecific Tetravalent Antibody for the Treatment of Multiple Myeloma

“…The bispecific, tetravalent antibody, RO7297089, which binds specifically to BCMA and CD16A (also known as FcγRIIIa), was generated for MM treatment (10) and tested in the phase 1 clinical trial in relapsed/refractory MM (RRMM, Study NCT04434469). CD16A is a transmembrane receptor expressed exclusively on natural killer (NK) cells and macrophages with high expression levels (11)(12)(13).…”

“…CD16A is a transmembrane receptor expressed exclusively on natural killer (NK) cells and macrophages with high expression levels (11)(12)(13). Engagement of both BCMA on malignant plasma cells and CD16A on NK cells triggers NK cell-mediated killing of BCMA-expressing malignant plasma cells, a process known as antibody-dependent cellular cytotoxicity (ADCC) (10). Macrophage-mediated phagocytosis (i.e., antibody-dependent cellular phagocytosis, ADCP) of malignant plasma cells may also be a mechanism of action (MoA) as CD16A is found on macrophages (14).…”