Abstract A146: FPI-2068: A novel anti-EGFR/cMET, alpha-particle emitting, radioimmunoconjugate for cancer therapy

Abstract

Abstract Introduction: FPI-2068, a targeted alpha therapeutic (TAT), consists of a humanized EGFR and cMET targeting bispecific antibody (FPI-2053) radiolabeled with actinium-225 [225Ac]. FPI-2068 leverages the EGFR/cMET co-expression in cancer (high vs. low in normal tissues) and internalizing nature of the receptors to deliver radionuclides into tumor cells. The primary tumoricidal mechanism of FPI-2068 is double-strand DNA breaks (DSB) induced by alpha radiation, which lead to cell death. Methods: FPI-2068 consists of FPI-2053 conjugated with a DOTA-chelate and radiolabeled with [225Ac]. FPI-2071 is the lutetium-177 analogue. The binding and internalization of FPI-2071 was studied in vitro using cancer cell lines (HT29 colorectal and H292, H441, H1975, HCC827 lung cancers). In vivo studies were performed in corresponding xenograft models. For biodistribution studies FPI-2071 was injected intravenously into mice and tumor/organ radioactivity was quantified ex vivo at selected timepoints. For therapeutic studies, a single dose of FPI-2068 was administered to groups of mice over a range from 92.5 to 740 kBq/kg. Explanted HT29 and H441 tumors from FPI-2068 treated mice were analyzed by immunoblotting to detect activation of DDR and cell death pathways. Results: FPI-2071 demonstrated in vitro binding to all cell lines tested, followed by internalization and retention of the radioisotope into target cells. The biodistribution profile of FPI-2071 showed low normal organ uptake in all xenograft models tested, while tumor uptake varied. The peak tumor uptake in each model was: H292 (~73 %ID/g), H441 (~38 %ID/g), HT29 (~30 %ID/g), HCC827 (~25 %ID/g) and H1975 (20 %ID/g). Delivery of FPI-2068 to target xenografts resulted in anti-tumor efficacy; treatment was well-tolerated by animals. Sustained tumor regression (>28 days) was generally observed at doses of 370 kBq/kg and 740 kBq/kg across models. Lower doses were tumor growth suppressive. FPI-2068 treatment resulted in a dose-dependent increase in pATM and pRad50 expression indicating activation of DDR pathways in HT29 and H441 xenografts. Formation of DSB (pH2AX) and the induction of apoptosis (cleaved caspase 3) was also observed, consistent with the proposed primary mechanism of action. Conclusions: FPI-2068 demonstrated its anti-tumor efficacy in colorectal and lung tumor xenograft mouse models. Single-dose administration of FPI-2068 led to prolonged tumor regression. FPI-2068 caused activation of the DDR pathway as well as apoptosis, suggesting an inability of the cellular machinery to repair the DNA damage induced by the alpha radiation. These data support initiation of clinical trials in patients with solid tumors. Citation Format: Sadaf Aghevlian, Sean Collens, Julie Metcalf, Natalie Grinshtein, John Forbes, Frank Comer, Darshan Dalal, Puja Sapra, Eric Burak. FPI-2068: A novel anti-EGFR/cMET, alpha-particle emitting, radioimmunoconjugate for cancer therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A146.