Abstract 1556: B7-H7-CD3 bispecific T cell engaging antibodies demonstrate potent anti-tumor activity in B7-H7+ preclinical tumor models

Abstract Background: B7-H7 is a B7 family member that suppresses T and NK cell activation through an inhibitory receptor, KIR3DL3, and stimulates immune cell activation through a distinct receptor, TMIGD2. B7-H7 is upregulated on tumor cells of many histological subtypes and is, therefore, explored as a novel tumor targeting antigen. NextPoint has developed two B7-H7-targeted CD3 bispecific antibodies, NPX372 and NPX387, to redirect T cell-mediated immunity toward B7-H7+ tumors. Both antibodies bind B7-H7 with similar avidity and block interaction with KIR3DL3, but induce the formation of distinct immune synapses. Methods: B7-H7 and CD3 binding were evaluated on-cells expressing human and non-human primate (NHP) versions of the proteins by flow cytometry. Bispecific antibody-mediated T cell activation was assessed using Jurkat reporter assays. Primary T cell activation was evaluated in vitro in co-culture assays with B7-H7+ tumor cell lines by flow cytometry and multiplex cytokine analysis. T cell redirected killing of B7-H7+ tumor cells was assessed using PBMC co-culture assays and flow cytometry. Finally, humanized mouse models were used to test the anti-tumor activity of both NPX372 and NPX387 in B7-H7+ tumor models in vivo. Results: NPX372 and NPX387 bound to both human and NHP B7-H7 and CD3. While both bispecific antibodies demonstrated similar on-cell avidity to B7-H7, NPX372 demonstrated stronger affinity for human CD3 compared to NPX387. Co-culture assays with Jurkat reporter cells and primary T cells demonstrated that both NPX372 and NPX387 could crosslink B7-H7 on tumor cells to CD3 leading to T cell activation. However, despite having a stronger affinity for CD3, NPX372 induced less cytokine production in primary T cell cultures with B7-H7+ tumor cells compared to NPX387. Both bispecific antibodies also induced potent T cell-mediated killing of multiple B7-H7+ tumor cell lines in vitro with similar potency. Finally, both NPX372 and NPX387 demonstrated anti-tumor activity in a B7-H7+ tumor model in vivo at clinically relevant doses that are tolerated in NHP toxicity studies. Conclusion: These data demonstrate that B7-H7 represents a novel tumor associated antigen for CD3 bispecific T cell engagement that can induce potent T cell-mediated anti-tumor immunity. Citation Format: Karishma Vekaria, Susannah Hewitt, Melissa W. Hayes, Emilien Loeuillard, Jamie Strand, Riale Gilligan, Maja Razlog, Emma Aeschliman, Quangvinh Tran, McKenna Lamb, Bijan Etemad-Gilbertson, Silvia Ferrati, Tatiana Novobrantseva, Matthew Rausch. B7-H7-CD3 bispecific T cell engaging antibodies demonstrate potent anti-tumor activity in B7-H7+ preclinical tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1556.