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 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 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 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 hinge cysteine residues (Cys-SH). Though affording a certain degree of stoichiometric control during conjugation, this protocol yields only low drug-loading ratios (DAR), 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 60 ADCs in clinical trials, but despite intense activity only two approved products (KadcylaTM and AdcetrisTM). It is accepted that the highly cytotoxic payload's off-target toxicity is what drives the adverse effects in ADCs. 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. Beck A, Goetsch L, Dumontet C, Corvaïa N. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017 May;16(5):315-337. doi: 10.1038/nrd.2016.268
2. Thomas A, Teicher BA, Hassan R. Antibody-drug conjugates for cancer therapy. Lancet Oncol. 2016 Jun;17(6):e254-62. doi: 10.1016/S1470-2045(16)30030-4
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