A novel anti-FGFR1 monoclonal antibody OM-RCA-01 exhibits potent antitumor activity and enhances the efficacy of immune checkpoint inhibitors in lung cancer models

  • Immunooncol Technol. 2024 Jul 26:23:100725. doi: 10.1016/j.iotech.2024.100725.
I Tsimafeyeu  1 ,  P Makhov  2 ,  D Ovcharenko  3 ,  J Smith  3 ,  Y Khochenkova  4 ,  A Olshanskaya  5 ,  D Khochenkov  4  6
Affiliations
  • 1. Bureau for Cancer Research - BUCARE, New York.
  • 2. Program in Cancer Signaling and Microenvironment, Fox Chase Cancer Center, Philadelphia.
  • 3. Altogen Labs, Austin, USA.
  • 4. N.N. Blokhin National Medical Research Center of Oncology, Moscow.
  • 5. Clinical Oncology Hospital No. 1, Moscow.
  • 6. Center for Medicinal Chemistry, Togliatti State University, Togliatti, Russia.
PMID: 39290712 DOI: 10.1016/j.iotech.2024.100725
Abstract

Background: Fibroblast Growth Factor receptor 1 (FGFR1) plays a crucial role in carcinogenesis. Exploring the combination of the novel humanized monoclonal anti-FGFR1 antibody OM-RCA-01 and immunotherapy was intriguing due to involvement of FGFR1 in mechanisms of resistance to checkpoint inhibitors.

Materials and methods: Lung Cancer A549, exhibiting distinct levels of FGFR1 expression, were cultured in basic FGF medium with OM-RCA-01 supplementation. The efficacy of antibody monotherapy was validated in a lung Cancer xenograft study. To investigate whether OM-RCA-01 could enhance the efficacy of immunotherapy in vitro and in vivo, mixed lymphocyte reaction/Staphylococcal enterotoxin B assays and FGFR1/programmed death-ligand 1-positive patient-derived xenograft model were established.

Results: The antibody effectively suppressed receptor phosphorylation, resulting in inhibited cell proliferation. OM-RCA-01 led to a substantial delay in tumor growth compared to non-specific immunoglobulin G in a xenograft study. The median tumor volume was 1048.5 mm3 and 2174 mm3 in the study and vehicle groups, respectively, representing a twofold difference in favor of the anti-FGFR1 antibody. In vitro, the combination of nivolumab and OM-RCA-01 resulted in higher levels of interferon gamma and interleukin-2 release compared with nivolumab alone. In vivo, pembrolizumab in combination with OM-RCA-01 produced a greater inhibitory effect on tumor growth compared with vehicle and pembrolizumab alone. The curve plateaued, indicating minimal tumor growth from day 16 onwards in the combination group. The OM-RCA-01 demonstrated no toxicity, even at therapeutic doses or higher doses.

Conclusions: Our preclinical studies demonstrate that OM-RCA-01 exhibits robust activity with minimal toxicity. Combining an anti-FGFR1 antibody with a checkpoint inhibitor may enhance the efficacy of both drugs. However, further studies are needed to elucidate the mechanism of this interaction.

Keywords
anti-FGFR1 monoclonal antibody; fibroblast growth factor receptor 1; immune checkpoint inhibitors; immunotargeted therapy.
Products