Antibody drug conjugates (ADCs) are finally becoming a mainstay cancer therapy but their rise to prominence has not been without setbacks. Following on from the initial approvals of Adcetris (in 2011) and Kadcycla (in 2013) there followed a period of clinical failures of ADCs due to a lack of both efficacy and unacceptable toxicity. However, the trickle of ADC approvals suddenly became a deluge in 2019 when the FDA approved three new ADCs to treat various cancers. ADCs use the exquisite specificity of antibodies to deliver a potent cytotoxin payload to cancerous cells but critically for solid tumours have failed to live up to their promise due to a number of critical limitations; low potency, poor/slow tumour penetration and poor tolerability. This has resulted in ADCs having a narrow therapeutic window in patients and toxicity profiles comparable with standard chemotherapy. Smaller antibody formats such as single chain Fvs (scFvs) have many advantages including rapid/deep tumour penetration and faster clearance from normal tissue. Despite this, their utilisation has been unsuccessful. Our technology, enables antibody fragments to have both a high drug to antibody ratio (DAR) but also overcomes the pharmacokinetic challenges of small antibody formats with judicious medicinal chemistry around the payload-linker, coupled with higher tissue penetration. This leads to a new class of products called Fragment Drug Conjugates (FDCs) We have developed bespoke scFv libraries ‘predisposed’ to high DAR conjugation based on the human VH5 human variable domain, a powerful ‘FDC Discovery Engine’, with more than 5 billion clones for identifying FDC products to any target. Focusing on gastric cancer, two candidates were discovered against a validated target expressed in gastro-intestinal cancer. Affinity maturation yielded derivatives with high affinities of 20-800pM. DAR 8 conjugates were obtained following bioconjugation with a potent tubulin inhibitor (MMAE) on a suitably designed linker to provide both solubility and PK modulation. Final FDC affinities of 100pM-2nM were obtained, in the preferred range needed for high tumour uptake and rapid tumour penetration. These two FDCs displayed picomolar cytotoxicity against tumour cell lines in vitro and had superior biophysical properties. One candidate demonstrated significant tumour cure efficacy at weekly dosing with high tolerability despite 10x more payload being administered compared to a conventional ADC.

Antibody fragment drug conjugates (FDCs): Overcoming the challenges of treating solid tumours

ACS Fall 2020 Virtual Meeting

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