Vaccine targeting IGF1R induces neutralizing antibody and robust anti-tumor activity in a syngeneic mouse colon cancer model

Background Insulin-like growth factors (IGFs) and their receptor (IGF1R) induce important cellular signalling that regulates cell proliferation, survival, and metabolism. Overexpression of IGF1R in cancers is associated with poor prognosis and resistance to conventional therapies, highlighting the need for innovative therapeutic strategy. In this study, we developed IGF1R vaccine candidates and evaluated their anti-tumor activity in a syngeneic mouse colon cancer model. Methods Recombinant proteins comprising different immune enhancers and computationally-predicted B-cell epitopes in the regions involved in IGF-IGF1R ligand-receptor interaction, intended to induce antibodies to block IGF-IGF1R interaction, were produced. Immunogenicity of the vaccine proteins was assessed in C57BL/6 mice by vaccination 6 times on days 0, 14, 28, 42, 49 and 56 using the proteins adjuvanted with CpG ODN 1826 and AS03. Serum samples were collected at multiple time points for determining anti-IGF1R antibody titers using ELISA as well as in vitro neutralization activity via blocking IGF1 binding to IGF1R using competitive ELISA. Anti-tumor efficacy of the vaccines was evaluated in a syngeneic MC38 mouse colon cancer model in C57BL/6 mice, which were vaccinated and inoculated subcutaneously with MC38 cells a week after the last vaccination. Mice administered adjuvant only were used as controls. Tumor growth was recorded twice a week till the end point. Results IGF1R vaccines induced robust humoral immune response as demonstrated by high titer of anti-IGF1R antibody. Importantly, serum samples collected from vaccinated mice demonstrated strong neutralizing activity, inhibiting IGF1 binding to IGF1R by up to 68% in a competitive ELISA. Two proteins which induced the highest antibody titer (i.e. 1:125,000) were further evaluated for their anti-tumor efficacy. In the anti-tumor study using the MC38 model, these two IGF1R vaccines suppressed the growth of tumors by 62% and 61%, respectively, at the study endpoint compared to controls ( p <0.01). Conclusions In summary, these findings establish proof-of-concept that IGF1R-targeting vaccines can elicit neutralizing antibodies that block IGF1 binding to IGF1R, thereby inhibiting the growth of tumors where IGF/IGF1R signalling plays critical roles. This result supports further investigation and optimization to improve these IGF1R vaccines to treat cancers dependent on IGF/IGF1R signalling.