Antibody Drug Conjugates

2. Antibody-drug Conjugates (ADC’s, also called immuno-conjugates) consist of a recombinant monoclonal antibody (MAb) covalently bound by a synthetic linker to a cytotoxic chemical. The main objective is to combine the pharmacological potency of “small” highly cytotoxic drugs (300 to 1,500 Da) and the high specificity of mAbs (150 kDa) for tumour-associated antigen targets.

Anti-neoplastic drugs (e.g. taxol, a microtubule inhibitor or irinotecan, a DNA damaging camptothecin drug) have demonstrated their ability to kill cancer cells, but generally with limited selectivity and highly toxic side-effects on normal tissues yielding only marginal therapeutic indices. On the other hand, approved monoclonal antibody (MAb) drugs (e.g. Herceptin/trastuzumab) have demonstrated their therapeutic utility to achieve significant clinical efficacy in malignancies with lower side effects. These are normally single agents, but often in combination with chemotherapy drugs. The use of unmodified mAbs as single agents can be 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 ADCs are by far the most promising.

Covalent conjugation of MAbs and drugs with synthetic chemical linkers is not a recent concept. In the 1960s, the use of ADCs in pre-clinical 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. Humanized antibodies such as trastuzumab, combined with more potent microtubule inhibitors led to the approval of 2nd generation ADCs such as HER2-targeted trastuzumab emtansine (Kadcyla) which became a clinical and commercial success in breast cancer. Further innovation around the linker-payload (switching to a camptothecin called exatecan) lead to the approval of a more effective HER2-targetting ADC called trastuzumab deruxtecan, which had greatly stimulated activity in this area. Despite these innovations, ADCs are intricate molecules to develop and their mechanism of action is complex (see figure below taken from [1]).

The main method for conjugating drugs to mAbs has been via the thiol side-chains of hinge cysteine residues (Cys-SH). Though affording a certain degree of stoichiometric control during conjugation, the DAR can be variable due mainly to the large mAb-drug conjugate becoming notoriously insoluble at higher drug loadings. The alternative method employs direct surface lysine conjugation to obtain an average ratio of 4, but with millions of permutations. More recent innovations include complex protein engineering approaches to obtain homogeneuous and specific DARs of 2 or 4, but still utilising large and bulky whole mAbs.

There are at least 100 ADCs in clinical trials, around 92 in advanced stages (Phase 2 and Phase 3 [2], but despite intense activity only 6 are approved for solid tumours [2]. It is accepted that the highly cytotoxic payload's off-target toxicity is what drives the adverse effects in ADCs [3]. Hence strategies such as Antikor's are needed to reduce normal tissue exposure and improve delivery kinetics.

Antikor's interest and expertise in the use of much smaller mAb fragments (eg, single-chain scFvs) to covalently attach anti-cancer drugs, began with PhotoBiotics in 2001. As an Imperial College spin-out company, they developed a novel way of specifically targeting photosensitiser payloads to tumours to improve the success of photodynamic therapy. The Company is now fully focussed on the much wider market opportunity of ADCs and has applied its technology and expertise using conventional cytotoxic payloads, whilst retaining its knowledge and capabilities in antibody engineering, synthetic chemistry and conjugation science.

References

1. Fu Z, Li S, Han S, Shi C, Zhang Y. Antibody drug conjugate: the "biological missile" for targeted cancer therapy. Signal Transduct Target Ther. 2022 Mar 22;7(1):93. doi: 10.1038/s41392-022-00947-7. PMID: 35318309; PMCID: PMC8941077.

2. Filis P, Zerdes I, Soumala T, Matikas A, Foukakis T. The ever-expanding landscape of antibody-drug conjugates (ADCs) in solid tumors: A systematic review. Crit Rev Oncol Hematol. 2023 Dec;192:104189. doi: 10.1016/j.critrevonc.2023.104189. Epub 2023 Oct 21. PMID: 37866413.

3. Saber H, Leighton JK. An FDA oncology analysis of antibody-drug conjugates. Regul Toxicol Pharmacol. 2015 Apr;71(3):444-52. doi: 10.1016/j.yrtph.2015.01.014