Abstract 3628: T cell-dependent bispecific antibody anti-CD79b/CD3 as a potential therapy for B-cell malignancies
Authors: Wang Peiyin , Hristopoulos Maria , Clark Robyn , Chen Yvonne , Ellerman Diego , Mathieu Mary , Spiess Christoph , Li Jessica , Chalouni Cecile , Sukumaran Siddharth , Stefanich Eric , Wallin Jeffrey , Li Robert , Zabka Tanja , Totpal Klara , Dennis Mark , Ebens Allen , Gould Stephen , Polson Andrew , Sun Liping Laura 
Published: July 2017

Abstract
T-cell recruiting bispecific antibodies and antibody fragments have been used to harness the cytotoxic potential of T cells for cancer treatment. We have adopted a knobs-into-holes antibody format and produced T-cell dependent bispecific antibodies (TDB), as full length, humanized IgG1 antibodies with natural antibody architecture, which allow one arm to target various B cell antigens while the other arm recruits T cells by binding to the CD3ϵ subunit of the T-cell receptor. One B cell antigen targeted is CD79b, a component of the B cell receptor complex, which has been clinically validated by an anti-CD79b antibody-drug conjugate (ADC) as a safe and effective therapeutic target for B cell malignancies (Leukemia 2015 Pfeifer et.al).
In the present work, we show that anti-CD79b/CD3 TDB is active against lymphoma cells with a wide range of CD79b antigen levels in vitro. In addition, anti-CD79b/CD3 TDB appears to be insensitive to the status of cellular signaling pathways in lymphoma cells as it is active against cell lines that are resistant to the BTK inhibitor ibrutinib or an anti-CD79b ADC with a cleavable tubulin inhibitor as the payload. In vivo, anti-CD79b/CD3 TDB administration inhibited tumor growth in B-cell lymphoma xenograft models and resulted in potent B-cell depletion in the blood and spleens in a humanized murine model.
To assess the safety of targeting CD79b with a T-cell recruiting bispecific antibody in non-human primates, a surrogate anti-cynoCD79b/CD3 TDB with comparable in vitro potency was produced with a target arm that recognizes cynomolgus monkey CD79b and the same anti-CD3 arm. In a single dose pharmacokinetic/pharmacodynamics/safety study, anti-cynoCD79b/CD3 TDB administration at 1mg/kg resulted in potent B cell depletion, as well as T cell activation and proliferation, which was assessed by flow cytometry on blood and lymphoid tissue and immunohistochemistry on lymphoid tissue. The pharmacokinetic properties of anti-cynoCD79b/CD3 TDB resembled that of IgG antibodies; though with a faster clearance likely due to CD79b antigen internalization and enhanced binding to CD3 when compared to previously described anti-CD20/CD3 TDB. Transient cytokine release was observed as elevated levels of IL-2, IL-6, IFN-gamma and TNF-alpha were detected within 24 hours following administration. Anti-cynoCD79b/CD3 TDB was well-tolerated in the majority of dosed animals without toxicologically significant findings.
Collectively, these preclinical data suggest anti-CD79b/CD3 TDB can be a potential therapeutic agent in B cell malignancies.
Citation Format: Peiyin Wang, Maria Hristopoulos, Robyn Clark, Yvonne Chen, Diego Ellerman, Mary Mathieu, Christoph Spiess, Jessica Li, Cecile Chalouni, Siddharth Sukumaran, Eric Stefanich, Jeffrey Wallin, Robert Li, Tanja Zabka, Klara Totpal, Mark Dennis, Allen Ebens, Stephen Gould, Andrew Polson, Liping Laura Sun. T cell-dependent bispecific antibody anti-CD79b/CD3 as a potential therapy for B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3628. doi:10.1158/1538-7445.AM2017-3628