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Immunotherapy

A BCMA/CD16A bispecific innate cell engager for the treatment of multiple myeloma

Leukemia volume 36, pages 1006–1014 (2022)Cite this article

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Abstract

Despite the recent progress, multiple myeloma (MM) is still essentially incurable and there is a need for additional effective treatments with good tolerability. RO7297089 is a novel bispecific BCMA/CD16A-directed innate cell engager (ICE®) designed to induce BCMA+ MM cell lysis through high affinity binding of CD16A and retargeting of NK cell cytotoxicity and macrophage phagocytosis. Unlike conventional antibodies approved in MM, RO7297089 selectively targets CD16A with no binding of other Fcγ receptors, including CD16B on neutrophils, and irrespective of 158V/F polymorphism, and its activity is less affected by competing IgG suggesting activity in the presence of M-protein. Structural analysis revealed this is due to selective interaction with a single residue (Y140) uniquely present in CD16A opposite the Fc binding site. RO7297089 induced tumor cell killing more potently than conventional antibodies (wild-type and Fc-enhanced) and induced lysis of BCMA+ cells at very low effector-to-target ratios. Preclinical toxicology data suggested a favorable safety profile as in vitro cytokine release was minimal and no RO7297089-related mortalities or adverse events were observed in cynomolgus monkeys. These data suggest good tolerability and the potential of RO7297089 to be a novel effective treatment of MM patients.

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Fig. 1: Schematic of RO7297089.
Fig. 2: Structure of the CD16A:anti-CD16A Fab complex.
Fig. 3: Cell killing of MM cells by RO7297089.
Fig. 4: RO7297089-induced target cell lysis: impact of CD16A receptor polymorphism and competing IgG.
Fig. 5: RO7297089-induced TNFα and IFNγ release.
Fig. 6: Pharmacological activities following weekly dosing of RO7297089 in cynomolgus monkeys.

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Data availability

For original data, please contact T.Ross@affimed.com or polson.andrew@gene.com. The protein structure has been deposited in the Protein Bank Database [accession number 7SEG].

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Acknowledgements

The authors gratefully acknowledge Reginald Delarosa, Gautham Rao, Rodney Prell, Fiona Zhong, Eunpi Cho, Patrick Twomey, Erin Christensen, James Cooper, Shannon Ruppert, and Joanne Adamkewicz at Genentech and study directors and contributing scientists at Labcorp for informative discussions and support on studies. The authors thank the Genentech Biomolecular Resources group for cloning and insect cell expression. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH.

Funding

All work was funded by Affimed or Genentech. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program was supported by the DOE Office of Biological and Environmental Research and by the National Institutes of Health, National Institute of General Medical Sciences (P41GM103393). Editorial support was provided by Meridian HealthComms, funded by Affimed.

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  1. These authors contributed equally: Satoko Kakiuchi-Kiyota, Thorsten Ross

Authors and Affiliations

  1. Genentech Research and Early Development, San Francisco, CA, USA

    Satoko Kakiuchi-Kiyota, Heidi Ackerly Wallweber, James R. Kiefer, Melissa M. Schutten, Adeyemi O. Adedeji, Hao Cai, Robert Hendricks, Sivan Cohen, Srividya Myneni, Luna Liu, Aaron Fullerton, Nicholas Corr, Lanlan Yu, Denise de Almeida Nagata, Shelly Zhong, Steven R. Leong, Ji Li, Rin Nakamura, Teiko Sumiyoshi, Jinze Li, Ayse Meric Ovacik, Bing Zheng, Mike Dillon, Christoph Spiess & Andrew G. Polson

  2. Affimed GmbH, Heidelberg, Germany

    Thorsten Ross, Susanne Wingert, Erich Rajkovic, Kristina Ellwanger & Uwe Reusch

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Contributions

SK-K, MMS and AOA designed, implemented, interpreted and reported nonclinical safety data (cytokines, cyno) and wrote related sections of the manuscript; AOA provided Fig. 6A. TR conceived and led the project and wrote and reviewed the manuscript. HAW and JRK designed, executed and interpreted structure-related experiments and wrote sections of the manuscript; JRK provided relevant figures. HC analyzed cynomolgus toxicokinetic data and wrote relevant sections of the manuscript. RH developed, validated, and executed assays for ADCC, ADCP, cynomolgus BA, cynomolgus ADA and cynomolgus sBCMA, wrote the relevant sections of the manuscript and provided Table S1 and Figs. S6 and S8. SC and SM developed, validated, and executed assays for ADCC and ADCP; SC wrote relevant sections of the manuscript and provided Figs. S6 and S8. LL developed and analyzed the cynomolgus sBCMA. AF designed, interpreted and reported cytokine and cynomolgus gene expression data, wrote relevant sections of the manuscript and provided Figs. 5 and 6B and Fig. S7. NC designed, executed and interpreted cytokine data and provided Fig. 5 and Fig. S7. LY designed, executed, interpreted, and reported cynomolgus gene expression data and provide Fig. 6B. DdeAN designed, interpreted and reported cynomolgus cytokine data and wrote the relevant section of the manuscript. SZ designed and managed the cynomolgus study. SRL designed, executed, interpreted and reported results for Fig. 3C, contributed FACS-based data for selecting cell lines for Fig. S8 and initial cytokine results for the experimental protocol Fig. 5. JiL designed, executed, interpreted and reported binding data in cynomolgus peripheral B cells, NK cells and PCs and wrote and reviewed the relevant sections of the manuscript and provided Fig. S10. RN and TS designed, executed, interpreted, and reported cell surface expression levels of BCMA in MM cell lines and primary frozen MM tumor cells, wrote the relevant sections of the manuscript and provided Fig S8. JinL designed and implemented the preclinical pharmacology and safety studies. BZ designed, executed, interpreted and reported the impact of APRIL and BAFF protein on binding and potency as well as the target expression profile in cynomolgus monkeys, helped design and review flow and plasma gene signature data, wrote and reviewed relevant sections of the manuscript and provided Figs. S7 and S10. MD designed, executed and interpreted SPR binding data, was responsible for antibody production, write relevant sections of the manuscript and provided Table S1. CS contributed to SPR and structure data interpretation, was responsible for antibody production, contributed to writing and reviewing relevant sections of the manuscript and provided Fig. 1. SW conducted experiments shown in Figs. 3A, D and 4, Table S2 and Figs. S2, S11 and S12 and performed data analysis. KE conducted experiments shown in Fig. 2D, performed data analysis and wrote sections of the manuscript; ER developed the affinity-matured anti-CD16A clone; UR characterized the anti-BCMA/anti-CD16A T and Ab, conducted experiments shown in Fig S1, performed data analysis and wrote sections of the manuscript. AP designed and interpreted preclinical experiments and wrote or reviewed all sections of the manuscript. All authors reviewed the manuscript and approved the submitted version of the manuscript.

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Correspondence to Andrew G. Polson.

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SK-K, HAW, JRK, MMS, AOA, JinL, HC, RH, LL, AF, NC, LY, DdeAN, SZ, SRL, JiL, RN, TS, AMO, BZ, MD, CS, SC, SM and AGP are employees of Genentech and TR, SW, ER, KE and UR are employees of Affimed.

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Kakiuchi-Kiyota, S., Ross, T., Wallweber, H.A. et al. A BCMA/CD16A bispecific innate cell engager for the treatment of multiple myeloma. Leukemia 36, 1006–1014 (2022). https://doi.org/10.1038/s41375-021-01478-w

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