The number of ADCs showing promising outcomes in clinical trials is rapidly growing, offering exciting opportunities for cancer patients. This presentation will outline the strategies for optimising key components of ADC design to further enhance the efficacy and tolerability of ADCs. Novel linker designs, payload selection, and DAR optimisation will be discussed.

Attempts to improve the clinical utility of ADCs have focused on linker-payload, such as novel payload classes, increased DARs and altering payload potency. However, limited efforts have been made to enhance payload delivery via antibody engineering. We demonstrate that incorporation of pH-dependent binding in an anti-cMET ADC can overcome the requirement for high cMET expression and potentially benefit a broader population of cancer patients with lower cMET levels.

IPH45 is a novel exatecan-based anti-Nectin-4 ADC. Its hydrophilic profile, high DAR and strong bystander effect translate into better efficacy in low Nectin-4 expressing-tumour preclinical models and a longer half-life than enfortumab vedotin (EV), an approved anti-Nectin-4 MMAE-based ADC. IPH45 has the potential to have a broader therapeutic index than EV, improved safety and dosing regimen, and the ability to overcome resistance to EV or MMAE-based ADCs.

CEACAM5 is a GPI glycoprotein expressed with a high prevalence on the cell surface of several tumoural indications while normal tissue expression is limited. We developed a novel CEACAM5 topoisomerase I inhibitor antibody-drug conjugate with a DAR of 8 which is stable in circulation in SCID mice and display an impressive overall response rate in single mouse trials of CRC, GC, and NSCLC PDX models.

Through an in-depth mechanistic methodology work supported by peptide mapping studies, we managed to develop a set of conditions allowing the highly selective modification of antibodies bearing N-terminal glutamate and aspartate residues. We demonstrated that this strategy did not alter their affinity toward their target antigen and produced an antibody-drug conjugate with subnanomolar potency and a bispecific antibody with the unprecedented 2:1 valency.

Chain exchange approaches based on engineered domain interfaces generates binder-format matrices for bispecific antibodies. Optimal bsAbs require combinations of compatible binders, optimised stoichiometries and formats. Chain-exchange can also generate ADC matrices that combine binders, formats, attachment-positions, and payloads. Analyses of a Her2-binding ADC matrix with payloads attached in different formats, positions and stoichiometries reveals that ‘format-defines-function’ applies not only to bsAbs but also to ADCs.

FDCs promise advantages over ADCs including tumour penetration and faster clearance. ANT-045 is a solid tumour cMET-targeted FDC demonstrating superior tumour cure efficacy and tolerability compared to the leading competitor ADC, in multiple models with supporting quantitative biodistribution, micro-distribution imaging, stability, and toxicology data. In a non-GLP NHP study, ANT-045 was well tolerated with a predicted human half-life ~12h supporting a viable clinical dosing strategy and a wide therapeutic window.

Bicyclic peptides (Bicycle molecules) offer a differentiated and innovative modality for targeted delivery of cytotoxic payloads into tumours. Bicycle molecules exhibit high potency and selectivity and may confer advantages over existing modalities, particularly their small size and favourable pharmacokinetics profile. Bicycle Therapeutics is conducting clinical evaluation of BT8009, a Bicycle Toxin Conjugate (BTC) targeting Nectin-4, and BT5528 targeting EphA2. Data demonstrating the potential of these molecules will be presented.

Antibody drug conjugates rely on advanced conjugation chemistry with a more or less defined drug-to-antibody ratio (DAR). We have developed an antibody format allowing for a rapid DAR=2 cargo loading by incorporation of a unique scFv that binds to a tag with high affinity. Mixing the bispecific antibody targeting both cells and a tag, with tagged cargo, leads to instant drug preparation and a stable antibody-drug conjugate formation. The drug loading and targeting strategy have been evaluated using an antibody targeting CD40 to optimise antigenic cargo delivery and subsequent immune and anti-tumour responses. We have also studied the role of the tag on immune responses alone. I will include unpublished data from the development of a CD40 agonistic antibody format based on the this bispecific technology for drug conjugate formation (currently under revision in Nature communications).

This presentation explores the development and engineering of soloMERs, a novel type of drug conjugate, and it potential for therapeutic applications outside cancer treatment.