Investigational antibody drug conjugates for solid tumors

Abstract

Key challenges the ADC field is facing, including potency and safety, can be addressed effectively by introducing novel research concepts with transformational potential for ADC development.

Preclinical Antitumor Efficacy of BAY 1129980—a Novel Auristatin-Based Anti-C4.4A (LYPD3) Antibody–Drug Conjugate for the Treatment of Non–Small Cell Lung Cancer

“…We used a fully human C4.4A-Ab coupled via cysteine residues and a noncleavable linker to a novel antimitotic auristatin W derivative to generate a C4.4A-ADC (BAY 1129980) and evaluated its therapeutic potential in vitro and in vivo (18). The microtubule-disrupting auristatin derivative was chosen due to the proven effectiveness of this effector class in the clinic (32). In addition, we confirm our previous findings (31) that N-carboxylalkyl-N-methyl auristatin W derivatives are highly efficacious microtubuledisrupting agents that can be optimized for reduced efflux properties and allow for stable linker attachment.…”

“…Multiple ADCs targeting various antigens in several cancer types are currently under evaluation in preclinical and clinical studies (39) and auristatin-based conjugates are utilized in approximately half of the ongoing clinical studies with ADCs (32). However, to our knowledge, there are only a few other ADCs in development for the treatment of NSCLC and none of them target C4.4A, making our approach unique.…”

Milatuzumab–SN-38 Conjugates for the Treatment of CD74+ Cancers

“…ADCs have been of considerable research interest for many years, but only recently peaked, primarily due to the clinical success of 2 conjugates prepared with socalled "supertoxic" agents that have subnanomolar potency, which replaced many of the earlier ADCs prepared using chemotherapeutic agents that had potencies in the nanomolar levels (40)(41)(42)(43)(44)(45)(46). However, drug potency or even its specific mechanism of action is not the only defining property that affords optimal performance of an ADC.…”

Long-term Tumor Regression Induced by an Antibody–Drug Conjugate That Targets 5T4, an Oncofetal Antigen Expressed on Tumor-Initiating Cells

“…Antibody-drug conjugates (ADC) constitute a therapeutic modality in which a cytotoxic agent is chemically linked to an antibody that recognizes a tumor-associated antigen (1). The basic strategy underlying ADCs is to combine the exquisite target selectivity of monoclonal antibodies with the potent cytotoxic activity of certain natural products and synthetic molecules, with the goal of generating agents that are highly efficacious and also safe.…”

“…Key considerations in generating an optimal ADC include target biology, antibody properties, linker chemistry, and payload characteristics. Notably, more than half of the ADCs in clinical development are based on auristatin, a synthetic analog of the natural product dolastatin-10 that inhibits tubulin polymerization and ultimately induces G 2 -M cell-cycle arrest and cell death at low picomolar intracellular concentrations (1)(2)(3)(4).…”