The novel nanobody-drug conjugate displays potent anti-cancer activity in solid tumours and is expected to help treat therapy-resistant tumours.
Under normal circumstances, the epidermal growth factor receptor (EGFR) regulates multiple cellular processes including but not limited to proliferation, differentiation, and survival. However, the overexpression of EGFR has been noted to affect aspects of carcinogenesis such as cell growth and invasion, angiogenesis, and metastasis.
Because abnormally active EGFR has been found to be an important contributor to oncogenic processes and tumorigenesis, clinicians have developed anti-EGFR therapies for cancer treatment. Anti-EGFR therapies include tyrosine kinase inhibitors and monoclonal antibodies that inhibit the EGFR pathway and are often used as an alternative treatment for patients who cannot tolerate or are ineligible for chemotherapy. Unfortunately, cancer patients treated with EGFR-targeted antibody therapy eventually develop epitope substitutions that abolish the binding of cetuximab and panitumumab, both of which are monoclonal antibodies, and results in anti-EGFR therapy resistance.
To overcome the problems of current antibody therapies, a team of researchers led by Professor Chen Shuqing and Professor Pan Liqiang at the Zhejiang University College of Pharmaceutical Sciences has developed a novel anti-cancer drug that can help address common mutation resistance in EGFR-targeting therapies. The drug, a biparatopic EGFR-targeting nanobody drug conjugate, consists of two fused anti-EGFR nanobodies that target two distinct epitopes.
An antibody-drug conjugate is a type of anti-cancer drug that links an antibody with cytotoxic molecules. It combines the targeting properties of the antibody and the killing effect of the chemotherapeutic drug. EGFR-targeted antibody-drug conjugates can specifically deliver cytotoxic molecules to the cytoplasm of EGFR-positive tumour cells by targeting antigens on the cell surface and internalising them into intracellular lysosomes fated for degradation. In doing so, the conjugate can help to overcome certain types of drug resistance induced by mutations in EGFR downstream signalling pathways.
Similarly, the new nanobody-drug conjugate developed by Prof. Chen and colleagues can deliver toxins into tumour cells to induce cytotoxic effects. Through a series of tests, the drug has been proven to exhibit superior endocytosis than cetuximab and can better deliver toxins into tumour cells. In addition, it was also able to evade targeting resistance hotspot mutations to cetuximab or panitumumab, effectively solving one of the major challenges of current EGFR-targeted antibody therapies.
Besides confirming that antibody-drug complements could activate complement-dependent cytotoxicity than conventional anti-EGFR antibodies, the researchers attempted to modify the Fc domain, the tail region of an antibody that interacts with Fc surface receptors, and some proteins of the complement system by introducing the E430G mutation. Their findings revealed that the mutation could not only promote the complement-dependent cytotoxicity effects of their antibody-drug conjugate but also synergise with the cytotoxicity of drug payload during cancer treatment. The researchers also explored the possibility of applying complement-dependent cytotoxicity enhancement to antibody-drug conjugates, from which they discovered that this enhanced EGFR-targeting antibody-drug conjugate displayed superior anti-cancer activity.
The study has brought new insights into the untapped potential of nanobodies to enhance complement-dependent cytotoxicity. But most importantly, as said by Professor Chen, their novel nanobody-drug conjugate “could significantly enhance targeted anti-cancer activity as a ‘biological missile’ and help address common mutation resistance in EGFR-targeted therapies,” which is “expected to offer more options for those patients with malignant tumour[s].”
Source: Fan et al. (2021). A multivalent biparatopic EGFR-targeting nanobody drug conjugate displays potent anticancer activity in solid tumor models. Signal Transduction and Targeted Therapy, 6, 320.