Abstract
Antibody-drug conjugates (ADCs) harness the highly specific targeting capabilities of an antibody to deliver a cytotoxic payload to specific cell types. They have garnered widespread interest in drug discovery, particularly in oncology, as discrimination between healthy and malignant tissues or cells can be achieved. Nine ADCs have received approval from the US Food and Drug Administration and more than 80 others are currently undergoing clinical investigations for a range of solid tumours and haematological malignancies. Extensive research over the past decade has highlighted the critical nature of the linkage strategy adopted to attach the payload to the antibody. Whilst early generation ADCs were primarily synthesised as heterogeneous mixtures, these were found to have sub-optimal pharmacokinetics, stability, tolerability and/or efficacy. Efforts have now shifted towards generating homogeneous constructs with precise drug loading and predetermined, controlled sites of attachment. Homogeneous ADCs have repeatedly demonstrated superior overall pharmacological profiles compared to their heterogeneous counterparts. A wide range of methods have been developed in the pursuit of homogeneity, comprising chemical or enzymatic methods or a combination thereof to afford precise modification of specific amino acid or sugar residues. In this review, we discuss advances in chemical and enzymatic methods for site-specific antibody modification that result in the generation of homogeneous ADCs.
Highlights
Antibody–drug conjugates (ADCs) are a class of targeted therapeutics, typically developed for the treatment of cancer
To maximise the ADC’s anti-tumour efficacy and safety, a number of key linker-antibody attachment attributes have been identified: (1) the attachment motif must be highly stable in circulation to avoid premature drug release, which can lower ADC efficacy and cause toxicity in healthy tissue;[38,39] (2) the number of linker-payloads per antibody should be optimised for potency without compromising safety;[40] (3) the location of attachment on the antibody should not interfere with the antibody’s function; and (4) the conjugation reaction should efficiently and selectively facilitate modification of the antibody in a controlled and consistent manner.[41]
In vitro studies showed that the more potent PBD cytotoxin dominated the cytotoxic properties of the ADC, this study demonstrated that varied functional moieties can be installed on cysteine-engineered antibodies
Summary
Antibody–drug conjugates (ADCs) are a class of targeted therapeutics, typically developed for the treatment of cancer. While interchain bonds are highly solvent exposed and may be reduced and/or modified by chemical methods, the intrachain bonds are buried within the globular fold of the protein and are unreactive to chemical modification unless harsh denaturing conditions are applied.[29] In contrast to IgG1, native IgG4 molecules can undergo dynamic Fab arm exchange which may reduce their efficacy in vivo and lead to undesired off-target effects This can be prevented through a S228P mutation in the hinge region of the heavy chain, as in the case of clinically approved ADCs Mylotargs and Besponsas.[30,31] Currently, all other approved ADCs utilise IgG1 antibodies
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