Abstract 15P
Background
Epidermal growth factor receptor inhibitors (EGFRi) commonly cause severe skin toxicity, particularly papulopustular eruptions. These lesions often lead patients to discontinue or reduce treatment. Current treatments mainly address symptoms, failing to prevent the initial trigger of toxicity and offering limited benefit . In our previous work, we developed a compound and method to prevent “on-target” skin toxicity by topically blocking the drug-receptor interactions of cetuximab and panitumumab at the site of toxicity. We have now successfully extended this approach to novel bispecific EGFR inhibitors, including amivantamab, petosemtamab, and izalontamab.
Methods
We employed several methods to evaluate the efficacy of SDT-011 in blocking bispecific EGFRi antibodies from binding to recombinant human EGFR (rhEGFR). Initially, an ELISA was conducted to assess the binding inhibition. To further investigate the functional implications of this blockade, MTT assays were performed in HaCaT and A431 cell lines to determine the reversal of EGFR inhibition. Additionally, flow cytometry was utilized to quantify the expression levels of EGFR on cell surfaces. To gain deeper insights into the mechanism of action, in silico docking experiments were conducted to understand how SDT-011 blocks amivantamab, petosemtamab, and izalontamab.
Results
SDT-011 demonstrated effective blocking of anti-EGFR bispecific monoclonal antibodies binding to EGFR, including amivantamab, petosemtamab, and izalontamab. SDT-011 prevented tEGFR internalization and inhibited the antiproliferative effects induced by EGFRi bispecific antibodies in keratinocyte cell lines. These findings suggest that SDT-011 effectively counteracts the effects of EGFRi bispecific antibodies in keratinocytes.
Conclusions
SDT-011 offers a promising approach for treating on-target skin toxicity by topically blocking EGFRi monoclonal and bispecific antibodies at the site of toxicity. By potentially reducing the incidence and severity of skin toxicities associated with EGFR inhibitors, SDT-011 could improve patients' quality of life and treatment compliance, ultimately enhancing the overall effectiveness of cancer therapies.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Israel Innovation Authority, NGT HealthCare II (“NGT”).
Disclosure
S. Merims: Financial Interests, Personal and Institutional, Full or part-time Employment, CSO: EMRIS Pharma. L. Aharonov: Financial Interests, Personal, Full or part-time Employment, CEO: EMRIS Pharma. Y. Hazut, L. Weinstein: Financial Interests, Personal, Full or part-time Employment: EMRIS Pharma. O. Benny: Financial Interests, Personal, Full or part-time Employment, CTO: EMRIS Pharma.