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Antibody-drug Conjugates

Antibody-drug Conjugates (ADC's, also called immuno-conjugates) consist of a recombinant monoclonal antibody (mAb) covalently bound by a synthetic linker to a given cytotoxic chemical. The main objective is to combine the pharmacological potency of "small" cytotoxic drugs (300 to 1,000 Da) and the high specificity of mAbs (150 kDa) for tumour-associated antigen targets.

Anti-neoplastic drugs have demonstrated their ability to kill cancer cells, but generally with limited selectivity and highly toxic side-effects on normal cells yielding only marginal therapeutic indices. On the other hand, approved antibody drugs have demonstrated their therapeutic utility to achieve significant clinical efficacy in malignancies, but often only in combination with small cytotoxic drugs. The use of unmodified mAbs as single agents is sub-optimal; currently they can only extend survival by a few months. In addition, many mAbs suffer from drug resistance due to mutations in cell-signalling pathways. Many strategies are being pursued to overcome this, but antibody-drug conjugates are the most promising.

Covalent conjugation of mAbs and drugs with synthetic chemical linkers is not a recent concept. In the 1960s, the use of antibody-drug conjugates in animal models was described in the literature, and in the 1980s, clinical trials were conducted with murine IgG-based antibody-drug conjugates. Many high profile failures led to innovations in antibody engineering and drug / linker technology.

The main method for conjugating drugs to mAbs has been via the thiol side-chains of cysteine residues (Cys-SH). Though affording a certain degree of stoichiometric control during conjugation, this protocol yields only low drug-loading ratios, due mainly to the large mAb-drug conjugate becoming notoriously insoluble at higher drug loadings.

PhotoBiotics' interest in the use of much smaller mAb fragments (scFvs) to covalently attach anti-cancer drugs, began at the beginning of the 21st Century, initially as a way of specifically targeting photosensitisers to tumours and improve the success of photodynamic therapy. The development and success of the Optilink technology platform allows many other chemotherapeutic and / or diagnostic moieties to be covalently attached to sc-Fvs, thus broadening the scope for novel antibody-drug conjugates based on antibody fragments rather than whole antibodies.