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JNJ-78306358 is a first-in-class bispecific antibody (bsAb), engineered using the Zymeworks Azymetric™ platform, to treat advanced stage solid tumors. Human leukocyte antigen G (HLA-G) is a non-classical major histocompatibility class I molecule with an immune tolerance role at the maternal-fetal interface. HLA-G has limited normal tissue expression, mainly detected in placenta and pituitary gland. However, HLA-G is expressed in multiple human cancers, with a potential role in cancer immune evasion. Comprehensive immunohistochemistry analysis of patient-derived tumors revealed high prevalence of HLA-G expression in renal cell carcinoma (RCC, 75%), ovarian (61%), colon (64%) and rectal cancers (40%), and moderate HLA-G expression prevalence in lung adenocarcinoma, endometrial, and pancreatic cancer. JNJ-78306358 induces HLA-G-expressing tumor cell killing via T cell redirection. This bsAb features an anti-HLA-G single-chain fragment variable (scFv) domain that binds with high affinity (KD ~ 13 pM) to HLA-G on tumor cells and a Fab domain that binds with weaker affinity (KD ~22 nM) to the epsilon subunit of the cluster of differentiation 3 (CD3ε). The immunoglobulin (Ig)G1 heavy chains feature Fc region mutations that disrupt interaction with Fcγ receptors. JNJ-78306358 demonstrated potent PBMC- and T cell-mediated in vitro cytotoxicity (EC50 10.4 - 442.3 pM) against endogenous membrane HLA-G-expressing tumor cell lines and absence of killing against cancer cells lacking HLA-G membrane expression, highlighting the specificity against antigen-expressing tumor cells. JNJ-78306358 exhibited hallmarks of T cell engagement in vitro, including T cell proliferation and cytokine release. In addition, JNJ-78306358 showed HLA-G-expression-dependent anti-tumor activity in mice (humanized with human donor CD3+ pan-T cells or human umbilical cord-blood-derived CD34+ hematopoietic stem cells [HSCs]) bearing cell line- and patient-derived tumors. In these xenograft models, a dose-dependent increase in CD4+ and CD8+ T cell infiltration into tumors was observed with complete tumor regressions at low doses of JNJ-78306358 (0.03 mg/kg). JNJ-78306358’s safety, tolerability and preliminary anti-tumor activity are currently being evaluated in a first-in-human phase I study in advanced stage solid tumors with high prevalence of HLA-G protein expression (NCT04991740). This antigen-targeting approach may address an unmet medical need in patients with tumors expressing HLA-G. Citation Format: Nataša Obermajer, Adam Zwolak, Kelly Van De Ven, Shana Versmissen, Aleksandra Brajic, Ted Petley, Dan Weinstock, Jason Aligo, Fang Yi, Stephen Jarantow, Keith Schutsky, Ken Tian, Angelilo Lorraine, Diana Alvarez Arias, Kristel Buyens, Vince Torti, Krista Menard, Katharine Rogers, Brian Geist, Marjolein Van Heerden, Gerald Chu, Bie Verbist, Maté Ongenaert, Julien Hasler, Kathryn Packman, Jacintha Shenton, Dirk Brehmer, Josh Lauring, Regina J. Brown, James Greger, Daphne Salick Ryan, Sanjaya Singh, Matthew V. Lorenzi, Laurie Lenox, Sylvie Laquerre. JNJ-78306358: A first-in-class bispecific T cell redirecting HLA-G antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND07. |
