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MULTIPLE MYELOMA, GAMMOPATHIES

Preclinical discovery and initial clinical data of WVT078, a BCMA × CD3 bispecific antibody

Leukemia volume 37, pages 1349–1360 (2023)Cite this article

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Abstract

B-cell maturation antigen (BCMA) is an ideal target in multiple myeloma (MM) due to highly specific expression in malignant plasma cells. BCMA-directed therapies including antibody drug conjugates, chimeric antigen receptor-T cells and bispecific antibodies (BsAbs) have shown high response rates in MM. WVT078 is an anti-BCMA× anti-CD3 BsAb that binds to BCMA with subnanomolar-affinity. It was selected based on potent T cell activation and anti-MM activity in preclinical models with favorable tolerability in cynomolgus monkey. In the ongoing first-in-human phase I dose-escalation study (NCT04123418), 33 patients received intravenous WVT078 once weekly at escalated dosing. At the active doses of 48–250 µg/kg tested to date (n = 26), the overall response rate (ORR) was 38.5% (90% CI: 22.6–56.4%) and the complete response rate (CRR, stringent complete response + complete response) was 11.5%, (90% CI: 3.2–27.2%). At the highest dose level tested, the ORR was 75% (3 of 4 patients). 26 (78.8%) patients reported at least one Grade ≥3 AE and 16 of these AEs were suspected to be drug related. 20 patients (60.6%) experienced cytokine release syndrome. WVT078 has an acceptable safety profile and shows preliminary evidence of clinical activity at doses tested to date.

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Fig. 1: BCMA × CD3 mediates T-cell activation and tumor cell lysis.
Fig. 2: In vivo activity of WVT078 at 3 mg/kg i.v. in cynomolgus monkeys.
Fig. 3: WVT078 displays favorable PK properties and is tolerated in patients at doses tested so far.
Fig. 4: Clinical activity of WVT078.
Fig. 5: Combination with a GSI enhances WVT078 activity in preclinical models.

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Data availability

Novartis will not provide access to patient-level data, if there is a reasonable likelihood that individual patients could be re-identified. Phase 1 studies, by their nature, present a high risk of patient re-identification; therefore, patient individual results for phase 1 studies cannot be shared. In addition, clinical data, in some cases, have been collected subject to contractual or consent provisions that prohibit transfer to third parties. Such restrictions may preclude granting access under these provisions. Where co-development agreements or other legal restrictions prevent companies from sharing particular data, companies will work with qualified requestors to provide summary information where possible.

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Acknowledgements

The authors thank all the participating sites, the patients participating in this clinical trial, and their families. The authors thank the staff at each participating institution who assisted with the study. The authors thank Gary Vanasse, Ryan Polli, Mirek Dostalek, Bernd Potthoff, Martine Duval, Jeanne Hardy, Carsten Krantz, Sema Kurtulus, Raina Duan, Michelle Coulson, Daher Ibrahim Aibo, Mike Daley, Brian Stoll, Stan Spence, Joni Lam, Melissa Ramones, Connie Hong, Lucia Huang, Brian Holmberg, Na Li, Barbara Brannetti and Gregory Moore for their contribution to the preclinical and clinical research. The authors also wish to thank Glenn Dranoff, Alice Shaw, Lilli Petruzzelli, David Steensma, Ulrich Bialucha, Juliet Williams, John Desjarlais, Francesco Hofmann and Jeffrey Engelman for their feedback and guidance.

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Author notes

  1. These authors contributed equally: Marc S. Raab, Yael C. Cohen, Fredrik Schjesvold.

Authors and Affiliations

  1. Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany

    Marc S. Raab

  2. Department of Hematology, Tel-Aviv Sourasky (Ichilov) Medical Center, Tel Aviv University, Tel Aviv, Israel

    Yael C. Cohen

  3. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Yael C. Cohen

  4. Oslo Myeloma Center, Department of Hematology, Oslo University Hospital, Oslo, Norway

    Fredrik Schjesvold

  5. Novartis Institutes for BioMedical Research, Cambridge, MA, USA

    Kimberly Aardalen, Adwait Oka, Kristin Henson, Gina Trabucco, Ana Carrion, Adonai Fessehatsion, Liqiong Fan, Jeffrey P. Stonehouse, John W. Blankenship, Brian Granda, Serena De Vita & Haihui Lu

  6. Department of Malignant Haematology, The Alfred Hospital, Melbourne, VIC, Australia

    Andrew Spencer

  7. NCT/UCC Early Clinical Trial Unit, Universitätsklinikum Carl Gustav Carus an der Technische Universität, Dresden, Germany

    Martin Wermke

  8. Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI, USA

    Anita D. Souza

  9. Winship Cancer Institute, Emory University, Atlanta, GA, USA

    Jonathan L. Kaufman

  10. Department of Hematology, Niguarda Hospital, Niguarda, Milan, Italy

    Anna Maria Cafro

  11. Hospital Universitario Marqués de Valdecilla (IDIVAL), Universidad de Cantabria, Santander, Spain

    Enrique M. Ocio

  12. Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan

    Noriko Doki

  13. Novartis Institutes for BioMedical Research, Basel, Switzerland

    Florent C. Bender & Pierre-Eric Juif

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  1. Marc S. Raab
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Contributions

KA, AO, KH, GT, AC and FCB contributed to the design, execution, data analysis and the result interpretation for preclinical studies. KA was responsible for the in vivo studies in mouse models. AO was responsible for the in vitro experiments. KH was responsible for the pharmacology study in cyno monkey. GT was responsible for the GSI combination experiments. AC was responsible for the characterization of binding affinities. FCB was responsible for the bioanalytical analysis. JWB and BG were responsible for the design of the BCMA Ab discovery and optimization campaigns, Ab engineering, data analysis, result interpretation. HL was responsible for the design of the preclinical studies, data analysis and interpretation. HL, BG and JPS led the selection of the lead molecule. SDV designed the clinical study, analyzed, and interpreted clinical data. PEJ analyzed clinical data. AF carried out the clinical study. LF analyzed and help interpreting clinical data. JPS supervised preclinical and clinical activities in the program. MSR, YC, FS, AS, MW, ADS, JLK, AMC, EMO, and ND had carried out clinical study and analyzed and interpreted clinical data. FS and MSR contributed to data collection, analysis, and interpretation of results, and writing the manuscript. All authors reviewed and contributed to writing the manuscript.

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Correspondence to Serena De Vita or Haihui Lu.

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Competing interests

MSR reports grants or contracts from BMS, Janssen, Sanofi, and Heidelberg Pharma; Consulting fees from BMS, AMGEN, GSK, Janssen, Sanofi/Genzyme, Pfizer, AbbVie and Takeda; Support for attending meetings and/or travel from BMS, Janssen, Sanofi, Heidelberg Pharma; Participation on a Data Safety Monitoring Board or Advisory Board from AbbVie. YCC reports consulting fees from Janssen, GSK, Amgen and Takeda; Payment or honoraria from Janssen, Amgen, Takeda, Medison and Neopharm; Participation on a Data Safety Monitoring Board or Advisory Board from Janssen. FS reports grants or contracts from Celgene, Janssen, Oncopeptides, Sanofi, GSK and Targovax; Payment or honoraria from Amgen, BMS, Takeda, Abbvie, Janssen, Novartis, SkyliteDX, Oncopeptides, Sanofi, Pfizer, Daiki-Sankyo and GSK; Participation on a Data Safety Monitoring Board or Advisory Board from Abbvie, GSK, Celgene, Takeda, Janssen, Oncopeptides and Sanofi. AS, AMC and ND have no conflicts of interest to declare. MW reports all support for the present manuscript from Novartis; Grants or contracts from Roche; Consulting fees from Immatics, Boehringer, Imcheck and Novartis; Payment or honoraria from Novartis, Pfizer and Bristol Myers Squibb; Support for attending meetings and/or travel from AstraZeneca; Participation on a Data Safety Monitoring Board or Advisory Board from ISA Therapeutics. ADS reports clinical trial support from Takeda, Novartis, Regeneron, TeneoBio, Abbvie, Janssen, Sanofi, Prothena and Caelum; Consulting fees from Janssen and Prothena; Participation on Advisory Board from BMS and Janssen. JLK reports grants or contracts from Janssen, Abbvie, Genentech, Amgen, BMS, Novartis, Heidelberg Pharma AG, Fortis Therapeutics and Sutro Pharmaceuticals; Consulting fees from Abbvie, BMS and Genentech; Participation on a Data Safety Monitoring Board or Advisory Board from Abbvie and Incyte. EMO reports payment or honoraria from Janssen, BMS, Sanofi, GSK, Oncopeptides, Takeda, Pfizer and Amgen; Support for attending meetings and/or travel from GSK, Janssen and BMS; Participation on a Data Safety Monitoring Board or Advisory Board from Janssen, Sanofi, GSK, Takeda, Amgen, Oncopeptides, Pfizer, Karyopharm and BMS. AO, KH, PEJ, AF, LF and JPS are employees of Novartis. GT, AC, FCB are employees and stockholders of Novartis. BG, SDV, HL are employees and stockholders of Novartis; Novartis may own patents/patent applications related to the subject matter disclosed herein, on which they are listed as one of the inventors. KA is employee of Novartis; Novartis may own patents/patent applications related to the subject matter disclosed herein, on which I am listed as one of the inventors.

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Raab, M.S., Cohen, Y.C., Schjesvold, F. et al. Preclinical discovery and initial clinical data of WVT078, a BCMA × CD3 bispecific antibody. Leukemia 37, 1349–1360 (2023). https://doi.org/10.1038/s41375-023-01883-3

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