1181 GEN1042-mIgG2a, an Fc-inert mouse-human chimeric variant of GEN1042 (DuoBody®-CD40x4–1BB), exhibits in vivo antitumor activity and peripheral immune modulation

• Published in: Journal for immunotherapy of cancer 2023-11, Vol.11 (Suppl 1), p.A1302-A1302
• Main Authors: Pilones, Karsten, Sette, Angelica, Nuermberger, Kristina, Luijten, Monique, Köhne, Maren, Wolthoorn, Jasja, Muik, Alexander, Fellermeier-Kopf, Sina, Ahmadi, Tahamtan, Tuereci, Oezlem, Sahin, Ugur, Jure-Kunkel, Maria, Adams, Homer
• Format: Article
• Language: English
• Subjects: Biological activity; Chemotherapy; Immunocompetence; Immunotherapy; Laboratory animals; Regular and Young Investigator Award Abstracts; Tumors
• ISSN: 2051-1426
• DOI: 10.1136/jitc-2023-SITC2023.1181

BackgroundGEN1042 (DuoBody®-CD40x4–1BB) is an investigational, novel, bispecific antibody that combines targeting and conditional activation of CD40 and 4–1BB on immune cells. We recently reported preclinical characterization and encouraging clinical activity of GEN1042 in solid tumors.1 2 Here, we investigated in vivo biological activity and mechanism of action of GEN1042 using the mouse-human chimeric, Fc-inert, surrogate antibody GEN1042-mIgG2a in immunocompetent human CD40/human 4–1BB double knock-in (hCD40/h4–1BB dKI) mice.MethodsBiological activity of GEN1042-mIgG2a, compared to GEN1042, was evaluated in vitro using cell-based reporter assays and human T-cell proliferation assays. hCD40/h4–1BB dKI mice implanted subcutaneously with syngeneic colorectal MC38 tumors were treated systemically with biweekly doses of GEN1042-mIgG2a or isotype control after tumor establishment, and pharmacokinetics, tumor growth and survival were investigated. In a parallel study, dose-dependent effects on circulating immune cells and plasma cytokines were investigated. Pilot studies were performed to investigate combination of GEN1042-mIgG2a with PD-1 blockade and a platinum-based chemotherapy doublet.ResultsComparable biological activity of GEN1042 and GEN1042-mIgG2a was confirmed in vitro. Biweekly dosing of 1 and 10 mg/kg GEN1042-mIgG2a resulted in largely maintained plasma concentrations within predicted levels in tumor-bearing dKI mice. Treatment with 1 or 10 mg/kg GEN1042-mIgG2a delayed tumor growth with observed significance on Day 12 after the start of treatment (p=0.0015 and p=0.0232, respectively) and 1 mg/kg GEN1042-mIgG2a significantly improved progression-free survival compared to control (p=0.001). Antitumor activity at 1 mg/kg GEN1042-mIgG2a was associated with favorable peripheral immune modulation, including an increased pool of memory T cells, upregulation of T-cell activation markers, induction of 4–1BB and CD86 on B cells, and changes in plasma cytokine concentrations. Preliminary data for a combination of 1 mg/kg GEN1042-mIgG2a with PD-1 blockade and a platinum-based chemotherapy doublet indicate enhancement of survival by treatment with this combination over GEN1042-mIgG2a alone in this model, resulting in complete tumor regressions in 3 out of 10 mice.ConclusionsGEN1042-mIgG2a, a mouse-human chimeric surrogate for GEN1042, incited dose-dependent in vivo antitumor activity in immunocompetent MC38 tumor-bearing hCD40/h4–1BB dKI mice and generated a pe