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Method for Novel Anti-Cancer Drug Development using Tumor Explants of Surgical Specimens
Published on: July 29, 2011
RN765C, a low affinity EGFR antibody drug conjugate with potent anti-tumor activity in preclinical solid tumor models
Oi Kwan Wong1,2, Thomas-Toan Tran1,3, Wei-Hsien Ho1,4
1Oncology R&D, Cancer Immunology Discovery Unit, Pfizer Inc., South San Francisco, CA, USA.
Abstract:
Epidermal growth factor receptor (EGFR) is a clinically validated target and often overexpressed in some solid tumors. Both EGFR tyrosine kinase inhibitors and ligand-blocking antibodies have been approved for treatment of NSCLC, head and neck cancers and colorectal cancers. However, clinical response is limited and often accompanied by significant toxicities due to normal tissue expression. To improve the effectiveness of targeting EGFR while minimizing the toxicities on normal tissues, we developed a low-affinity anti-EGFR antibody drug conjugate (ADC), RN765C. Potent in vitro cytotoxicity of RN765C, with nanomolar to subnanomolar EC50, was observed on a panel of cancer cell lines expressing moderate to high level of EGFR. In contrast, RN765C was less effective in killing normal human keratinocytes, presumably due to its lower receptor expression. Mechanistically, RN765C has multiple modes of action: inducing payload mediated mitotic arrest and cell death, blocking EGFR pathway signal and mediating antibody dependent cell cytotoxicity. In preclinical studies, a single dose of RN765C at 1.5-3 mg/kg was generally sufficient to induce tumor regression in multiple cell line and patient-derived xenograft models, including those that are resistant to EGFR-directed tyrosine kinase inhibitors. Our data support further investigation of RN765C in the clinic to treat EGFR expressing solid tumors.
Insights
A novel low-affinity anti-epidermal growth factor receptor (EGFR) antibody drug conjugate, RN765C, shows potent anti-tumor activity and reduced toxicity in preclinical models. This conjugate offers a promising new strategy for treating EGFR-expressing solid tumors.
Area of Science:
- Oncology
- Pharmacology
- Immunotherapy
Background:
- Epidermal growth factor receptor (EGFR) is a validated target in several solid tumors, including NSCLC, head and neck, and colorectal cancers.
- Current EGFR-targeting therapies (TKIs, antibodies) have limitations including clinical response variability and significant toxicities due to normal tissue expression.
- There is a need for improved strategies to target EGFR effectively while minimizing off-target toxicities.
Purpose of the Study:
- To develop and evaluate a novel low-affinity anti-EGFR antibody drug conjugate (ADC), RN765C, for improved EGFR-targeted cancer therapy.
- To assess the in vitro and in vivo efficacy and safety profile of RN765C in preclinical models of EGFR-expressing solid tumors.
Main Methods:
- RN765C was developed as a low-affinity anti-EGFR ADC.
- In vitro cytotoxicity was assessed on cancer cell lines and normal human keratinocytes.
- Mechanisms of action including payload-mediated cell death, pathway signaling blockade, and antibody-dependent cell-mediated cytotoxicity (ADCC) were investigated.
- In vivo efficacy was evaluated in cell line and patient-derived xenograft models.
Main Results:
- RN765C demonstrated potent in vitro cytotoxicity (nanomolar to subnanomolar EC50) against EGFR-expressing cancer cell lines.
- RN765C showed reduced efficacy against normal human keratinocytes, suggesting improved selectivity.
- Multiple mechanisms of action were confirmed, including payload delivery, EGFR pathway inhibition, and ADCC.
- A single dose of RN765C induced significant tumor regression in various preclinical models, including those resistant to TKIs.
Conclusions:
- RN765C is a promising anti-EGFR ADC with potent anti-tumor activity and a potentially improved safety profile.
- RN765C exhibits multiple mechanisms of action, contributing to its efficacy.
- These preclinical findings support the further clinical investigation of RN765C for treating EGFR-expressing solid tumors.
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