• Target Characterization: Expression and Internalization Profile
• Design Considerations for Heme vs. Solid Tumor Indications
• Payload Selection (Bystander vs. Non-Bystander Payloads)
• Future Directions and Novel ADC Formats

The inherent complexity of antibody-drug conjugates (ADCs) is a double-edged sword that provides opportunities to perfect therapeutic action while also increasing confounding factors in therapeutic failures. In this work, we discuss how payload delivery in solid tumors can be optimized by engineering ADC characteristics to match target properties such that a maximum number of tumor cells are targeted with a therapeutically active concentration of payload at tolerated doses.

Traditionally, physiological thiol gradient is used as a trigger for the drug release from the antibody-drug conjugate (ADC) containing a disulfide-based linker. A novel concept exploiting this physiological phenomenon to design a new class of cleavable linker with no disulfide bond is presented. To support the concept, favorable stability in human serum and selective intracellular drug release in the context of ADCs generated from an anti-human folate receptor alpha antibody and the newly designed drug-linker adduct, were confirmed. Furthermore, preliminary experimental data to support the proposed drug release mechanism from the ADC are discussed.

Glucocorticoids (prednisone, dexamethasone) are part of the standard-of-care treatment regimen for B-cell malignancies (e.g., R-CHOP or hyper-CVAD). However, systemic administration of glucocorticoids is associated with multiple side effects. ABBV-319 is an antibody-drug conjugate that consists of a potent glucocorticoid receptor modulator (GRM) agonist payload. ABBV-319 was designed with three mechanisms of action including delivery of GRM payload, CD19 inhibition, and antibody-dependent cellular cytotoxicity. Our data showed that ABBV-319 demonstrated pronounced anti-tumor activity in preclinical models of B-cell malignancies including double/triple-hit lymphoma or relapse/refractory diffuse large B-cell lymphoma. These data support further evaluation of ABBV-319 in Phase I clinical trial (NCT05512390).

Fucosyl-GM1 (FucGM1), a glycolipid overexpressed in the majority (>70%) of small cell lung cancer (SCLC) cases with minimal to no expression in normal tissues, has shown promise as a target for immunotherapy. SC134, a FucGM1 specific GlyMab, not cross-reacting with GM1 nor other normal gangliosides, exhibits avid tumor targeting and efficient internalization. SC134- ADC creation based on covalent conjugation to Deruxtecan demonstrated potent in vitro and in vivo SCLC killing, warranting further development for SCLC therapy. Drug delivery by other cancer-targeting GlyMabs will also be presented, consolidating the notion that tumor-associated glycans remain attractive targets for ADC development.

This talk presents ADC mathematical models incorporating both antigen-positive and antigen-negative cells. Simulations suggest that response to ADC treatment might not be durable when antigen-positive and antigen-negative cells grow independently. However, stromal-targeting ADCs could overcome this limitation, as antigen-positive stromal cells may be recruited into the tumor. Additionally, we demonstrate that ADCs with more permeable payloads and less stable linkers may enhance efficacy in cases of heterogeneous target expression.

Will provide a regulatory roadmap outlining the regulatory requirements for ADC therapeutics, from discovery to first-in-human trials and marketing approval.

Toxicity is the primary reason for ADC attrition. To improve the tolerability of B7-H3 targeted ADCs, we describe a multipronged approach involving site-specific drug conjugation, Fc silencing, optimization of drug-linker length. and post-conjugation purification. The lead ADC, m276-SL-PBD, eradicated large PDX tumors and improved overall survival. By combining judicious ADC engineering with personalized therapy through cancer-payload matching, we describe a path for the development of safe and effective ADCs.

Nanofitins are small protein scaffolds used as building blocks to form novel compounds with profiles adjusted to need. Affilogic formed drug conjugates with short half-life, high tumor uptake, and multiple functions in one single molecule.