Incorporation of new approaches in ADC design yield compounds with improved efficacy and tolerability. These new approaches include advanced antibody engineering, novel bioconjugation technologies, and tumor-selective payload release and activation chemistries that provide differentiated outcomes when compared to clinical benchmarks against known targets. Evaluation of these differentiated ADCs to “old” targets provides validation of the new designs for use in developing ADCs to “old” and “new” targets alike.

The past several years have seen dramatic growth in the number of approved ADCs, particularly for solid tumors. These approved agents have unique properties tailoring them to their specific target. However, there are several notable features shared among these agents, particularly related to the dosing and payload properties. Here, we’ll present the common features from current agents and how we can apply these lessons to develop even more effective therapeutics.

MRG003 is a novel antibody drug conjugate comprised of a humanized anti-EGFR antibody to the monomethyl auristatin E (MMAE) via a valine-citrulline linker. In Phase I clinical study evaluating the safety, tolerability, preliminary anti-tumor activity, and pharmacokinetics, MRG003 showed a manageable safety profile in patients with advanced solid tumors and demonstrated promising antitumor activity in patients with EGFR-positive nasopharyngeal cancers and squamous cell carcinomas of head and neck.

Sacituzumab govitecan (SG) was developed as a novel antibody drug conjugate for Trop-2 overexpressing tumors. SG utilizes a novel linker (CL2A) which afforded several key attributes, including increased payload to antibody ratio and release of payload extracellularly. SG has demonstrated activty clinically and is now approved for treatment of metastatic triple negative breast cancer and metastatic urothelial cancer, with additional tumors under study.

Affibody molecules are small engineered alternative scaffold affinity proteins that can be site-specifically loaded with cytotoxic drugs creating homogenous conjugates with a desired drug-to-carrier ratio. The presentation will explore the targeting of different cancer-relevant receptors, as well as the impact of affibody-carrier architecture, drug load, and peptide-linker composition on the biodistribution and in vitro and in vivo cytotoxic efficacy.

Glycans are excellent tumor targets. Notably, the same glycan expressed on a range of glycoproteins/lipids allows mAbs to target multiple antigens some of which can internalize whilst others are retained on the cell surface. Our mAbs can be potent ADCs but also retain ADCC/CDC activity and can cause membrane perturbation resulting in direct cell lysis. Additionally, Avidimab increases the avidity of any mAb and results in improved tumor killing. 

Most antibody-drug conjugates (ADCs) approved for the treatment of cancer contain protease-cleavable linkers, however, the identity of the various endosomal compartments responsible for cleavable ADC processing remains undefined. In agreement with the current model of ADC processing, a METxMET cleavable ADC is preferentially processed in late endosomes, however, we also find that a significant fraction is processed by recycling endosomes. This presentation will provide insights into the relationship between trans-endosomal trafficking and ADC processing and suggest that receptors that preferentially recycle to the plasma membrane via recycling endosomes might be suitable targets for cleavable ADCs.

The Araris’ site-specific and 1-step linker conjugation technology aims at generating safe and highly potent ADCs without the need for antibody engineering prior to linker-payload conjugation. We developed a very stable anti-CD79b-MMAE ADC with this technology showing a 4-6-fold higher therapeutic index compared to polatuzumab-vedotin in preclinical models. Our ADC may represent a safe and efficacious alternative for the treatment of patients with diffuse-large B-cell lymphoma (DLBCL).

Antibody-drug conjugates (ADCs) with PBD (pyrrolobenzodiazepine) dimers as the conjugated cytotoxic agent are dose-limited due to high potency and toxicities of PBDs. We developed a novel HER2-directed ADC, DHES0815A, with a reduced potency PBD (PBD-monoamide) to achieve dosing in the linear PK range for improved efficacy and tolerability. DHES0815A was efficacious in HER2+ breast and gastric cancer models and in HER2-low breast cancer (BC) models. The HNSTD in cynomolgus monkey was 12 mg/kg.  Preclinical efficacy and safety data and Phase 1 results in HER2+ BC for DHES0815A will be presented.

To achieve a preferential activation of ADCs in tumor versus healthy tissues we developed ADCs with novel linkers which are efficiently and selectively cleaved by the tumor associated protease legumain. Additional tuning of the physicochemical profile of the active metabolite resulted in highly potent ADCs against different targets. A favorable safety profile with regard to neutropenia, thrombocytopenia and liver toxicity could be shown in preclinical studies.

Heterobifunctional chimeric molecules that effect the intracellular degradation of specific proteins offer several potential advantages over conventional small-molecule inhibitors. However, they are also relatively large compounds that often possess molecular characteristics which may compromise oral bioavailability and/or in vivo pharmacokinetic properties. The conjugation of these chimeric entities to monoclonal antibodies to enable alternate delivery options will be discussed.

• The FORCE platform was developed for the targeted delivery of oligonucleotide-based therapeutics to treat neuromuscular disorders.  
• Highlighting the design and modularity of the platform.  
• Presenting the delivery and potency across various disease models