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Published on: May 12, 2023
A human IgG-like bispecific antibody co-targeting epidermal growth factor receptor and the vascular endothelial
Zhiguo Chen1,2, Wei Xie1, Desmond Omane Acheampong1
1a State Key Laboratory of Natural Medicines, Life Science & Technology, China Pharmaceutical University , China.
Abstract:
Both Epidermal Growth Factor Receptor (EGFR) and the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) play critical roles in tumorigenesis. We hypothesized co-targeting EGFR and VEGFR2 using a bispecific antibody might have significant therapeutic potential. Here,we designed and produced a human IgG-like bispecific antibody (Bi-Ab) based on the variable regions of cetuximab (an anti-EGFR antibody) and mAb-04 (an anti-VEGFR2 antibody developed in our lab) . The Bi-Ab was found to inhibit the proliferation, survival and invasion of cancer cells via ablating phosphorylation of receptor and downstream signaling. In vivo efficacy was demonstrated against established HT-29 and SKOV-3 xenografts grown in nude mice. Studies revealed our Bi-Ab was able to restrain xenografted tumor growth and prolong survival of mice through inhibiting cell proliferation,promoting apoptosis and anti-angiogenesis. In contrast to cetuximab or mAb-04 alone, our Bi-Ab exhibits enhanced antitumor activity and has equal or slightly superior activity to their combination (Combi). It shows promise as a therapeutic agent, especially for use against tumors EGFR and/or VEGFR2 over-expressing malignancies.
Insights
A novel bispecific antibody targeting both Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) demonstrated significant antitumor activity in preclinical models, inhibiting tumor growth and improving survival.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) are key drivers of tumor development.
- Co-targeting these receptors presents a potential therapeutic strategy.
Purpose of the Study:
- To design and evaluate a bispecific antibody (Bi-Ab) targeting both EGFR and VEGFR2.
- To assess the in vitro and in vivo efficacy of this novel Bi-Ab.
Main Methods:
- A human IgG-like bispecific antibody was engineered using variable regions from cetuximab (anti-EGFR) and a novel anti-VEGFR2 antibody.
- In vitro assays assessed cancer cell proliferation, survival, and invasion.
- In vivo studies utilized HT-29 and SKOV-3 xenografts in nude mice.
Main Results:
- The bispecific antibody inhibited cancer cell proliferation, survival, and invasion by blocking receptor phosphorylation and downstream signaling.
- In vivo, the Bi-Ab significantly restrained tumor growth and prolonged survival by reducing proliferation, promoting apoptosis, and inhibiting angiogenesis.
- The Bi-Ab showed enhanced antitumor activity compared to individual antibodies and comparable or superior activity to their combination.
Conclusions:
- The developed bispecific antibody targeting EGFR and VEGFR2 is a promising therapeutic candidate.
- This approach holds potential for treating malignancies overexpressing EGFR and/or VEGFR2.
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