Tsimafeyeu I, Makhov P, Ovcharenko D, Smith J, Khochenkova Y, Olshanskaya A, Khochenkov D
Bureau for Cancer Research - BUCARE, New York.
Program in Cancer Signaling and Microenvironment, Fox Chase Cancer Center, Philadelphia.
Immunooncol Technol. 2024 Jul 26;23:100725. doi: 10.1016/j.iotech.2024.100725. eCollection 2024 Sep.
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.
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 and , mixed lymphocyte reaction/Staphylococcal enterotoxin B assays and FGFR1/programmed death-ligand 1-positive patient-derived xenograft model were established.
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 mm and 2174 mm in the study and vehicle groups, respectively, representing a twofold difference in favor of the anti-FGFR1 antibody. , the combination of nivolumab and OM-RCA-01 resulted in higher levels of interferon gamma and interleukin-2 release compared with nivolumab alone. , 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.
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.
成纤维细胞生长因子受体1（FGFR1）在肿瘤发生过程中起着关键作用。由于FGFR1参与了对检查点抑制剂的耐药机制，探索新型人源化抗FGFR1单克隆抗体OM-RCA-01与免疫疗法的联合应用很有意义。
在添加OM-RCA-01的碱性成纤维细胞生长因子培养基中培养FGFR1表达水平不同的肺癌A549细胞。在肺癌异种移植研究中验证了抗体单药治疗的疗效。为了研究OM-RCA-01是否能增强免疫疗法的疗效，建立了混合淋巴细胞反应/葡萄球菌肠毒素B试验以及FGFR1/程序性死亡配体1阳性患者来源的异种移植模型。
该抗体有效抑制受体磷酸化，从而抑制细胞增殖。在异种移植研究中，与非特异性免疫球蛋白G相比，OM-RCA-01导致肿瘤生长显著延迟。研究组和载体组的肿瘤体积中位数分别为1048.5立方毫米和2174立方毫米，表明抗FGFR1抗体具有两倍的优势。此外，与单独使用纳武单抗相比，纳武单抗与OM-RCA-01联合使用导致更高水平的干扰素γ和白细胞介素-2释放。同样，与载体和单独使用派姆单抗相比，派姆单抗与OM-RCA-01联合使用对肿瘤生长产生了更大的抑制作用。曲线趋于平稳，表明联合组从第16天起肿瘤生长最小。即使在治疗剂量或更高剂量下，OM-RCA-01也未显示出毒性。
我们的临床前研究表明，OM-RCA-01具有强大的活性且毒性极小。将抗FGFR1抗体与检查点抑制剂联合使用可能会增强两种药物的疗效。然而，需要进一步研究来阐明这种相互作用的机制。
