Abstract

The traditional chemotherapy drug has been used as a standard cancer treatment, however it has resulted a modest survival benefit and damaged non-cancerous cells. Thus, the novel strategies which can improve selectivity and specificity in chemotherapy are urgently needed. Antibody drug conjugate (ADC) combines monoclonal antibody and cytotoxic drug is a potential regimen as targeted therapy. However, the heterogeneous mixtures has been observed using the current ADC methods. Here, we develop the strategy for generation a stable ADC utilising modified single chain antibody fragment (scFv) containing azide group for click chemistry reaction with alkyne containing cytotoxic drug. This research focused on targeting prostate cancer as a model disease utilising targeting prostate specific membrane antigen (PSMA) receptor which is overexpressed in all prostate cancer stages. The unnatural amino acid para-azido phenyl alanine (pAzF) has been successfully incorporated into anti-PSMA J591 scFv and specifically bound and internalised into PSMA positive cancer cells. This mutant scFv were also successfully conjugated into a linker containing cyclo-alkyne, DBCO-PEG4-DBCO as a model for creating ADC through copper-free click chemistry reaction. This bioconjugation method is promising as a versatile strategy for generating a stable ADC to improve therapeutic efficacy in cancer treatment.

Highlights

  • Cancer is a non-communicable disease that is estimated to rank as the leading cause of death worldwide

  • We focused on prostate cancer as a model disease by targeting prostate-specific membrane antigen (PSMA) receptors using an antiPSMA J591 antibody

  • We used pAzF providing azide functionality, which was incorporated at the N-terminus of J591 anti-PSMA scFv

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Summary

Introduction

Cancer is a non-communicable disease that is estimated to rank as the leading cause of death worldwide. It has been reported that there were 19.3 million incidences of cancer worldwide in 2020 and 10 million deaths (GLOBOCAN, 2020). Cancer development is associated with the accumulation of genetic mutations and epigenetic changes resulting in the loss of control in cellular growth of cancer cells. These cancer cells can invade normal tissues and organs, and spread throughout the body (Hanahan and Weinberg, 2011; Sharma et al, 2009). According to a report in 2017, there are around 30 monoclonal antibodies that have been approved and are marketed for the treatment of various types of cancers (Falzone et al, 2018).

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