Next-Generation ADCs Strive to Overcome Toxicities, Payload Problems

ADC with graduation cap/Nicole Bean for BioSpace

Pictured: An antibody-drug conjugate with a graduation cap over a soft background/Nicole Bean for BioSpace

Pharmaceutical companies are clamoring to add antibody-drug conjugates to their portfolios as the number of clinical trials explodes and the next generation rises.

Antibody-drug conjugates (ADCs) are biotherapeutics comprised of a monoclonal antibody designed to recognize an antigen on a target cell, a potent cytotoxic payload that triggers cell death and a linker binding the antibody and payload together. They are developed and used to treat various cancer indications.

“ADCs are a better chemotherapy,” said Joe Catanzaro, senior biotech analyst at Piper Sandler & Co. “There will always be efforts to move away from chemotherapy, and if you can replace chemotherapy, that obviously opens up a multitude of opportunities.”

Chemotherapy is notorious for causing deleterious side effects due to its lack of specificity. ADCs are effectively targeted chemotherapy, delivering cancer-killing material directly to malignant cells.

Jake Van Naarden, president of Loxo Oncology at Eli Lilly, which recently agreed to acquire ADC player Mablink Biosciences, said the rampant success of AstraZeneca and Daiichi Sankyo’s Enhertu could be driving the uptick in ADC interest because the industry wants to replicate those results. He likened it to the race to find PD-1-like targets that can repeat the success of Merck’s Keytruda.

Nathan Tumey_Binghamton University
Nathan Tumey

Nathan Tumey, associate professor at the School of Pharmacy and Pharmaceutical Sciences at Binghamton University, concurred, saying, “The clinical success of this product breathed life into the ADC field in a way that I haven’t seen in many years.”

In 2022, 57 ADCs entered Phase I clinical trials, a 90% increase over 2021, as reported by Clinical Leader. Researchers estimate that over 100 ADCs are being investigated across the spectrum of tumor types in various stages of clinical development.

An Evolving Science

ADCs are not a new technology. The first clinical trials involving an ADC were underway in the 1980s, with the first approval, for Pfizer’s Mylotarg (gemtuzumab ozogamicin) in acute myeloid leukemia (AML), coming in 2000. Mylotarg was subsequently withdrawn from the market after confirmatory trials failed to show benefit and raised safety concerns. A lower dose of the drug, with a different dosing schedule, was greenlit in 2017 for CD33-positive AML.

What differentiates next-generation ADCs from those currently on the market, Tumey said, is the incorporation of novel features including site-specific conjugation, new payload mechanisms and new antibody formats.

“These features are usually designed to expand the therapeutic window or push into new therapeutic indications,” he said.

Sung Joo Lee, CEO of Orum Therapeutics, pointed to the success of Enhertu as a driver of next-gen ADCs.

“Enhertu is basically an old antibody with an old linker with a different payload,” Lee told BioSpace. “That [payload] made a huge difference.”

First approved in 2019, Enhertu is indicated for breast, non-small cell lung and gastric cancers. In a comparison between Enhertu and Kadcyla—an older generation ADC—published on Enhertu’s website, nearly 83% of HER2+ breast cancer patients treated with Astra and Daiichi Sankyo’s drug saw their tumors shrink compared to 36% of those treated with Kadcyla.

Experts caution that there are challenges with ADCs that still need to be overcome, including toxicities and the tumor microenvironment itself.

Tumey said there are still a lot of questions about what drives ADC toxicity. Previously, it was believed that the main driver was premature payload release, but he said this is no longer considered the main or only issue.

“Even very, very stable ADCs have toxicity problems,” Tumey said. “Developing an understanding of the molecular basis for ADC toxicity would be a major step forward.”

Catanzaro added that another challenge is the limited number of tumor-specific antigens in solid tumors.

Joseph Catanzaro_Piper Sandler
Joe Catanzaro

Class of the 2020s

France-based Mablink is using its PSARLink platform to improve the delivery of ADCs. Mablink’s science is based on the foundation that the hydrophobicity of the cytotoxic drugs used in ADCs degrades the pharmacological properties of the antibody when bound to it. This can cause systemic toxicity or damage to healthy cells and tissues in the body and premature release of the payload before the ADC encounters the cells it is designed to target.

“Mablink has come up with a clever way to shield or protect the payload when it’s conjugated to the antibody,” Kristin Bedard, vice president of biologics at Loxo Oncology, told BioSpace.

MBK-103, Mablink’s lead asset, targets folate receptor alpha, an overexpressed protein found in many solid tumors, including ovarian and non-small cell lung cancers. In animal studies, MBK-103 demonstrated anti-tumor activity in colorectal and ovarian cancer models.

Orum is taking a different approach with ORM-6151, an anti-CD33 antibody-enabled GSPT1 degrader being developed to treat AML and patients with high-risk myelodysplastic syndromes. BMS paid $100M upfront for the novel ADC earlier this month. 

“We decided to work on GSPT1 because it’s a great target for AML,” Lee said. “Unlike toxins, GSPT1 degraders are very good at killing AML cells, but not good at killing hematopoietic stem cells.”

Jake Van Naarden_Eli Lilly
Jake Van Naarden

Orum presented preclinical data for ORM-6151 at the American Association for Cancer Research’s annual meeting in April demonstrating robust in vitro activity in AML models across a variety of clinical features and desirable pharmacologic properties. The FDA has granted approval for Phase I clinical trials to begin. 

Van Naarden said the primary question before the field is: Is Enhertu an outlier, or can it be replicated? “I think we don’t know,” he said. “The degree to which I think any one company is willing to sort of back the truck up in ‘ADC Land’ in some ways is a reflection of their conviction” that its success can be repeated.

The general consensus among the experts interviewed by BioSpace is that the future of this space looks bright and full of innovation.

“ADCs before were like black and white,” Lee said. “Now, it’s the era of color TV.”

Hayley Shasteen is a freelance science writer based in Northeastern Ohio. You can reach her at hayleyshasteen@gmail.com or follow her on LinkedIn.

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