Zymeworks Presents New Data from Multiple Preclinical Development Programs at 2024 American Association for Cancer Research Annual Meeting - Seite 2

Key Results:

• Leveraging Azymetric, bioconjugation, analytical mass spectrometry, and high throughput functional screening, a workflow for the rapid generation and characterization of bispecific ADCs was established to identify optimal format, paratope, and valency.
• A library of 48 bispecific ADC molecules co-targeting FRα and NaPi2b was rapidly generated covering multiple paratopes, antibody formats, and valency bins (1+1, 2+1, 2+2). Functional screening of the library across multiple cancer cell lines expressing FRα and/or NaPi2b revealed ranges in binding, internalization, and cytotoxicity that were dependent on epitope, valency, and format geometry.

Development of three-dimensional cancer cell line spheroid models for the in vitro functional characterization of cytotoxic antibody-drug conjugates
Abstract: 3127
Session Category: Experimental and Molecular Therapeutics
Session Title: Antibody-Drug Conjugates

Antibody-drug conjugates are an effective class of cancer therapeutics comprised of a linker-payload conjugated to a monoclonal antibody targeting a TAA, to enable the delivery of the cytotoxic payload to cancer cells. Current standard in vitro monolayer models do not sufficiently reflect in vivo tumor tissue complexity, particularly in consideration of the interaction between protein-based therapeutics such as antibodies in a three-dimensional (3D) environment. To address this, methodology to yield in vitro 3D spheroid models from cancer cell lines in a rapid, robust, and uniform manner was developed. Subsequently methods were integrated to evaluate the tissue penetration capability and cytotoxic activity of structurally distinct antibodies or ADCs bearing various payload classes targeting multiple TAAs.

Key Results:

• A readily implementable method for the rapid generation of cancer cell line spheroids was established and applied to over 50 distinct immortalized cancer cell lines derived from more than 10 tissue types, demonstrating varying morphological features with a success rate of >95%.
• In vitro assays were developed to evaluate the spheroid penetration capability and 3D cytotoxic activity of multispecific antibodies and ADCs, enabling the interrogation of various antibody formats and payload classes.
• These 3D models and assays serve as valuable functional tools that provide improved translation between in vitro and in vivo activity, supporting the characterization of therapeutic ADC candidates and their pipeline advancement.