Engineering Antibody-Drug Conjugates

This presentation will unveil the discovery process and comprehensive characterisation of the antibody component in AZD5335, AstraZeneca's novel folate receptor alpha-targeted, TOP1 inhibitor ADC. Currently in clinical development for ovarian cancer treatment (FONTANA, NCT#05797168), AZD5335 offers the potential for a significant advancement in FRa-targeted therapy. The talk will highlight the critical research phase of development, emphasising the rigorous down-selection process that yielded a potent, robust, and highly developable candidate drug.

This talk examines antibody-oligonucleotide conjugates, using BrainshuttleTM-ASO to deliver antisense oligonucleotides (ASOs) to the brain. We'll cover design, stability, and developability, culminating in in vivo activity data. A comprehensive overview from concept to application is presented.

The payloads currently employed in ADCs are limited in diversity and are sensitive to developing resistance. High off-tumour toxicity furthermore leads to a narrow therapeutic window. We have rationally designed a novel kinase degrader payload that targets a tumour-driving cell cycle kinase. The degrader payload was conjugated to various clinically validated antibodies to generate efficacious Degrader Antibody Conjugates (DACs). These can be applied in solid cancers such as prostate cancer.

Tagworks developed a cleavage reaction (Click-to-Release) to control drug activity in vivo. It enables on-target extracellular ADC cleavage through a reaction with a trigger given in a second step, expanding the target scope to non-internalising receptors. And it enables off-target deactivation of radioimmunotherapeutics by selective radiolabel cleavage and clearance from circulating mAbs, decreasing bone marrow toxicity. This contribution covers the preclinical development of anti-TAG72 ADC TGW101, for which a Phase-I has been initiated (NCT06959706), and anti-HER2 RIT TGW211.

Antibody Fragment Drug Conjugates (FDCs) promise many advantages over ADCs, including rapid tumour penetration and systemic clearance. Our approach enables high-DARs whilst retaining effective binding and other favourable biophysical properties. Our platform develops scFvs in context with complex linker-payload moieties. Our lead ANT-045 demonstrates superior tumour cures in cMET-high, moderate and low CDX/PDX gastric cancer models and better tolerability compared to leading competitor ADCs. New products based on our learnings will also be covered.

VelaVigo has developed robust proprietary target discovery and multispecific antibody technology platforms to deliver first-in-class (FIC) bispecific ADC programs. Two programs are showcased in this presentation. One is a FIC bispecific ADC targeting both CD79b and CD20, with preclinical data demonstrating superior efficacy compared to Polatuzumab Vedotin (PV) in both PV sensitive and resistant models, and excellent tumour inhibition in PDX model of Richter's syndrome. The other is a FIC bispecific anti-CDH17/CLDN18.2 ADC therapy, potentially addressing the limitation of targeting CLDN18.2 or CDH17 alone. Both programs also show favorable PK and tox profiles in rat and cyno, and excellent developability making it a strong candidate for further CMC development.

Targeted therapies have revolutionised the management of hematologic malignancies; however, the lack of disease-specific antigens restricts the treatment of especially myeloid malignancies. At Cimeio, we generated a state of the art CD45 ADC, which selectively depletes malignant AML cells, while the healthy hematopoietic system is protected through editing the antibody’s epitope in CD45. Our anti-CD45 ADC demonstrates full tumour elimination in vitro and in vivo, while hematopoiesis is fully preserved by engineering/shielding approach.

ADCs selectively deliver drugs to target cells, but when and where do ADCs release their drug payloads? We developed a fluorogenic platform for real-time imaging of ADC behaviour in cells, focusing on payload release. To achieve this, we designed dual-activatable fluorophores that switch fluorescence OFF to ON in response to two key events simultaneously: 1) subcellular localisation in acidic endolysosomal compartments, and 2) linker cleavage by proteases. This approach provides unprecedented mechanistic insights, guiding rational ADC design for enhanced efficacy.