AACR, Cancer Treatment and the Promise of Antibody-Drug Conjugates

cancer cells

Pictured: Illustration of migrating cancer cells/iStock, Christoph Burgstedt

The red hot antibody-drug conjugate market continues to fire on all cylinders and this week’s American Association for Cancer Research (AACR) annual meeting in San Diego once again drove home the impact the technology is having in oncology.

With their ability to deliver highly cytotoxic molecules directly to cancer cells, antibody-drug conjugates (ADCs) as a class of anti-cancer drugs are transforming oncology. Nonetheless, these novel agents come with their own challenges, including toxicities and payload problems.

Among the highlights at AACR was a TROP2-directed ADC developed by Merck and Kelun-Biotech that showed promising disease control and potentially extended survival in heavily pretreated patients with gastric or gastroesophageal junction cancer. Preliminary data from a Phase I/II study evaluating the ADC, which uses a novel linker to connect the antibody with the payload, were presented at AACR by Jordi Rodon, associate professor of investigational cancer therapeutics at the University of Texas MD Anderson Cancer Center.

“It is interesting to note the change in antitumor activity and safety profile that results from changing payloads and linkers, even among ADCs aiming at the same target,” Rodon said in a statement. “One of the big results of this trial is that, by using a different linker-payload combination, we did not see the interstitial lung diseases associated with other ADCs.”

Linkers used in ADC development can be classified as cleavable and non-cleavable. The linker in Merck and Kelun-Biotech’s investigational ADC, SKB264, is cleaved by pH changes in the vicinity of the tumor and by enzymes inside the cancer cells, allowing the payload to exert its anti-cancer effect in a targeted manner.

A global Phase III study is being planned to evaluate SKB264 in comparison to the current standard of care in patients with at least three prior lines of therapy in gastric or gastroesophageal junction adenocarcinomas. The ADC is also being evaluated in a Phase III study for triple-negative breast cancer and in a Phase II trial for non-small cell lung cancer and other advanced tumors.

Merck obviously sees the potential in this technology. In a deal worth up to $208 million, the pharma company last week bought preclinical startup Abceutics with the goal of developing safer ADCs and minimizing their off-target effects on healthy cells. Abceutics’ payload-binding selectivity enhancer technology is designed to seek out and neutralize stray payload molecules from ADCs, which in turn could spare healthy cells from the off-target effects of treatment.

Currently, ADCs are in the second generation of development, according to Jake Van Naarden, president of Eli Lilly’s Loxo Oncology division. The second generation of ADC technology is “much more intentional” about therapeutic choices, including payload classes and other factors such as bystander effects, Van Naarden told BioSpace.   

With next-generation ADCs, Eli Lilly, Daiichi Sankyo and other biopharma companies are striving to overcome toxicities and payload problems. In particular, the next wave of ADCs could treat evasive solid tumors.

At this week’s AACR annual meeting, Elevation Oncology presented preclinical proof-of-concept data for a differentiated ADC that targets HER3, which is overexpressed across a range of solid tumors, while Tubulis presented preclinical proof-of-concept data for two lead next-generation ADC candidates targeting solid tumors—both of which are optimized for minimal off-target toxicity.

Last week, AstraZeneca and Daiichi Sankyo’s ADC Enhertu became the first FDA-approved tumor-agnostic HER2-targeted therapy authorized for the treatment of solid tumors in adults who have undergone prior systemic treatment. Enhertu works by seeking out and binding to the HER2 protein, which is typically found on several solid tumors.

Finally, this week Bristol Myers Squibb-backed TORL BioTherapeutics announced that it closed a $158 million oversubscribed Series B-2 funding round, which will help advance its pipeline of novel ADCs that includes a first- and potentially best-in-class candidate that targets the claudin 6 (CLDN6) protein. TORL-1-23 is being trialed for CLDN6-positive, platinum-resistant ovarian cancer, with a Phase II trial slated to start in the second half of 2024.

With so much activity in the space, both in terms of clinical trial results and business deals, we will undoubtedly be hearing much more about ADCs in the months and years ahead.

Greg Slabodkin is the news editor at BioSpace. You can reach him at greg.slabodkin@biospace.com. Follow him on LinkedIn.     

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