Advances in antibody drug conjugates’ (ADCs) drug design are enabling biologics manufacturers to develop more effective next-generation antibody-based therapeutics. Speaking at the recent Antibody Drug Conjugates meeting, scientists from Zymeworks and Debiopharm outlined their approaches and results.
Zymeworks, known for its asymmetric heterodimer platform to generate bispecific antibodies, is building a mix-and-match ADC platform. It maximizes product opportunity by enhancing the functionality of each of the ADC components to generate well-differentiated, clinically meaningful targets, according to the company.
The topoisomerase ADC platform that Paul Moore, PhD, CSO, highlights is built on camptothecin “with moderate potency and strong bystander activity; linkers of traceless, plasma-stable, cleavable peptides; and conjugation using thiol-maleimide chemistry to balance stability, safety and anti-tumor activity.”
As key points, Moore advises:
- Leveraging clinical learnings to drive design features
- Optimizing antibody selection for ADCs through functional screening
- Employing biparatopic antibody design to enhance internalization
Zanidatamab zovodotin (AW49), for non-small-cell leukemia and breast cancer, is the company’s most advanced candidate, and is in pivotal trials. Zanidatamab is an anti-HER2 biparatopic antibody that induces HER-2 clustering and complement-dependent cytotoxicity. “What’s interesting,” Moore says, “is that it can actually bind to the same HER-2 molecule [by targeting epitopes on the target that do not overlap].” It crosslinks HER-2 molecules efficiently, he adds.
Adding antibody “results in profound anti-proliferative activity and supports extended functions like complement-dependent cytotoxicity,” he says, noting that the result is better anti-tumor activity because of the clustering.
“There is no one-size-fits-all solution,” Moore says. “A toolbox of ADC technologies is required.”
Multilink™ platform
One of those tools may be the new linker payload platform Debiopharm has developed. Called Multilink™, it is based on a cleavable peptide that enables fast—but not premature—payload release, high stability, and good solubility to prevent aggregation. It allows several payloads to be attached to each linker for a high antibody-to-drug ratio.
“The cleavable peptide is unique,” Leo Marx, PhD, medicinal chemistry project manager, oncology, says. “Multilink is compatible with different cytotoxic drugs.”
The company achieved proof-of-concept with trastuzumab, an anti-HER2 antibody. Preclinical studies show Multilink increases cytotoxicity and improves tumor regression.
In mouse studies, tumor volume after 49 days was approximately half its original size with Trastuzumab Multilink (T-Multilink) with mertansine (DM1), but had grown four-fold when treated with the same compound without the linker. Comparable studies with T-Multilink-auristatin F showed complete tumor regression by about day 25, while treatment without the linker allowed the tumor to approximately triple in size.
“Multilink is a powerful technology to tackle cancers with low antigen expression,” Marx says. Debiopharm is using it to develop “novel, potent, stable, and safe ADCs for various antibodies.”
