New study aims to reduce unwanted toxicity in cancer therapy

However, undesired delivery of toxins to healthy cells remains problematic, and ADCs often cause severe side effects by killing cells in healthy tissues.

Joseph Balthasar, BS '91 & PhD '96, David and Jane Chu Endowed Chair in Drug Discovery and Development and professor of pharmaceutical sciences, has received a new $1.8 million R01 grant from the National Cancer Institute (NCI) to develop an “inverse targeting” strategy to increase the safety and efficacy of anti-cancer ADCs.

“Inverse targeting” was introduced in the 1990s by Balthasar and his PhD advisor at the University at Buffalo, Ho-Leung Fung, PhD. In this method, anti-drug antibodies are employed to alter the pharmacokinetics of anticancer drugs, preventing distribution of the drugs to healthy tissues.

By blocking drug distribution to healthy tissues, inverse targeting decreases the undesired toxicity of cancer therapy, allowing higher drug doses to be administered safely, and enabling improved anti-cancer efficacy.

The new NCI project, titled “Enhancement of ADC selectivity by inverse targeting: Mechanistic studies and optimization,” applies the inverse targeting concept to optimize therapy with anti-cancer ADCs. Balthasar and his students have developed a new class of drugs, termed payload-binding selectivity enhancers (PBSEs), that decrease the toxicity of ADC therapy without negatively impacting efficacy.

 “The inverse targeting strategy may improve the safety and efficacy of all ten ADCs on the market, and the approach may be applied to more than 100 ADCs in current clinical development," Balthasar says.

Balthasar and his students recently submitted patent applications relating to their strategy, and they have launched a start-up company, Abceutics Inc., to pursue clinical development of new PBSEs developed in the Balthasar lab.

The new project adds to Balthasar’s current work, which includes support from two separate $1.8 million NCI R01 grants that evaluate new strategies to deliver protein toxins to the cytoplasm of targeted cancer cells (Catch and Release Immunotoxins: CAR-Bombs for cancer) and new strategies to increase antibody distribution in solid tumors (Pharmacokinetic strategies to increase monoclonal antibody uptake, distribution, and efficacy for treatment of solid tumors).

Balthasar credits several members of his lab and collaborating scientists as key contributors. Dhaval Shah, PhD '10, associate professor of pharmaceutical sciences, and Marilyn Morris, PhD ’84, SUNY Distinguished Professor and chair of pharmaceutical sciences, have joined Balthasar as a co-investigators on the new NCI grant. Other key contributors include Dr. Bruce Molitoris, distinguished professor of medicine and physiology at Indiana University, Brandon Bordeau, PhD '20, postdoctoral associate, and graduate students Jue (Joy) Gong and Toan Duc Nguyen.

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