Abstract 1072P
Background
While 4-1BB has shown preclinical promise as an immuno-oncology target, classical 4-1BB agonists have demonstrated limited success in clinical trials due to modest efficacy or severe hepatotoxicity. EpCAM is homogeneously expressed on the surface of cancer cells in many solid tumor indications. DuoBody-EpCAMx4-1BB (BNT314/GEN1059) is an Fc-inert immunomodulatory bispecific antibody (bsAb) designed to boost antitumor immune responses through EpCAM-dependent 4-1BB agonistic activity.
Methods
Target binding and functional activity of DuoBody-EpCAMx4-1BB was assessed by flow cytometry, cell-based reporter assays, and primary human lymphocyte/tumor cell-co-culture assays. Proof-of-principle in vivo studies were conducted using the murine MC38 tumor model. Non-clinical safety was assessed in cynomolgus monkeys.
Results
DuoBody-EpCAMx4-1BB bound to EpCAM on tumor cells and 4-1BB on activated T cells. By cross-linking target-expressing cells, DuoBody-EpCAMx4-1BB induced 4-1BB agonistic activity, which was conditional on binding to EpCAM due to its inert IgG1 Fc domain. In co-culture with EpCAM+ tumor cells, DuoBody-EpCAMx4-1BB dose-dependently enhanced activation of CD4+ and CD8+ T cells in anti-CD3-stimulated PBMCs from both healthy donors and cancer patients. Furthermore, DuoBody-EpCAMx4-1BB enhanced proliferation and cytokine secretion of activated healthy donor T cells and increased CD8+ T-cell mediated killing of EpCAM+ tumor cells in vitro. In ex vivo assays using tissue samples of patient-derived lymphocyte-infiltrated EpCAM+ tumors, DuoBody-EpCAMx4-1BB enhanced CD8+ T-cell and NK-cell expansion. An Fc-inert EpCAMx4-1BB bsAb exhibited antitumor activity in mice. DuoBody-EpCAMx4-1BB was well-tolerated in cynomolgus monkeys at doses up to 50 mg/kg (QWx5).
Conclusions
Through conditional 4-1BB agonistic activity, DuoBody-EpCAMx4-1BB enhanced T-cell activation, proliferation, and effector functions in vitro and ex vivo. In a murine model, an Fc-inert EpCAMx4-1BB bsAb promoted antitumor activity in vivo. It is intended to investigate the clinical safety and preliminary antitumor activity of DuoBody-EpCAMx4-1BB in patients with solid tumors in a first-in-human trial.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
BioNTech SE, Genmab A/S.
Funding
BioNTech SE, Genmab A/S.
Disclosure
S. Fellermeier-Kopf, A. Imle, K.B. Nuermberger, M. Köhne, A. Toker, C. Janaitis, A. Muik, Ö. Türeci, U. Sahin: Financial Interests, Personal, Full or part-time Employment: BioNTech SE; Financial Interests, Personal, Stocks/Shares: BioNTech SE. A. Ioan-Facsinay, A.M. Diks, L. Guelen, M. Houtkamp, S.M. Burm, J. Gamse, D. Satijn, T. Ahmadi, K. Kemper, E. Breij: Financial Interests, Personal, Full or part-time Employment: Genmab; Financial Interests, Personal, Stocks/Shares: Genmab.
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