Drug Developers Enhance ADCs with Immune System

The antibody-drug conjugate (ADC) market has seen rapid growth, expanding from $1 billion to $10 billion in yearly sales between 2015 and 2023, with projections reaching $28 billion by 2028, according to Evaluate. This growth is driven by ADCs' ability to deliver cytotoxic payloads directly to tumor cells, yet they are not curative, noted Tim Lowinger, Senior Vice President and Chief Science and Technology Officer at Mersana Therapeutics. Despite prolonging life and extending progression-free survival, reemergence of the disease remains a challenge.

As of February 2024, there are 15 approved ADCs, with many more in development. Drug developers are now exploring immunostimulatory ADCs (iADCs), also known as immune-stimulating antibody conjugates (iSACs), to build on the success of traditional ADCs. Immunotherapies have already proven effective in cancer treatment, and delivering these therapies via ADCs could enhance their precision in targeting tumor cells while sparing normal ones, said Jane Chung, President and Chief Operating Officer at Sutro Biopharma.

The enthusiasm for iADCs is partly fueled by the success of checkpoint inhibitors, which essentially release the immune system's brakes, allowing it to attack cancer cells, explained Nathan Tumey, Associate Professor at Binghamton University’s School of Pharmacy and Pharmaceutical Sciences. iADCs have the potential to amplify this effect by "stepping on the gas" of the immune response. Some cytotoxic payloads in current ADCs are also known to induce immunostimulatory cell death by generating more neoantigens in tumors, prompting companies like Pfizer to combine auristatin-based ADCs with checkpoint inhibitors for a synergistic effect.

Biopharma companies are exploring various pathways to activate the innate immune system. Mersana Therapeutics, for example, is working on a stimulator of interferon genes (STING) agonist. While STING activation has anti-cancer effects, it has been challenging because systemic activation can be toxic. Mersana’s approach uses ADCs to activate STING only after binding to tumor cells. Their lead asset, currently in Phase I trials, targets multiple HER2-positive solid tumors using a novel antibody instead of the commonly used trastuzumab, potentially allowing for combination with existing cytotoxic ADCs without competition for the same binding site.

Tallac Therapeutics, based in Burlingame, CA, has developed TAC-001, a TLR9 agonist ADC in Phase I/II trials for solid tumors. Unlike most ADCs that carry small molecule payloads, Tallac’s platform can conjugate an oligonucleotide to an antibody, broadening its therapeutic modalities beyond cytotoxicity. CEO Hong Wan highlighted the potential for a durable response and increased safety and tolerability due to TLR9 being part of the innate immune system and expressed predominantly on immune cells.

South San Francisco-based Sutro Biopharma, in collaboration with Astellas, is employing a dual conjugation strategy, combining chemotherapy and PD1 immune activators on an antibody to reduce tumor volume and activate the immune system, said Hans-Peter Gerber, Chief Scientific Officer at Sutro. Balancing the ratios between these elements is crucial, and Sutro’s technology allows precise adjustments.

Despite the promise, the path for iADCs has been fraught with challenges and failures. Notably, Silverback Therapeutics and Bolt Therapeutics experienced setbacks with similar treatments targeting HER2, leading to program discontinuations. Additionally, a Novartis-developed HER2-targeting iSAC failed in a Phase I trial for non-breast malignancies.

Dan Chancellor, Vice President of Thought Leadership at Norstella, pointed out that common targets like TLR-7, -8, -9, and STING have yet to achieve success with any therapy, indicating that iADC technology is still in its infancy. However, Tumey believes that the field’s early missteps, particularly targeting immunologically cold tumors like breast cancer, should shift focus to areas where checkpoint inhibitors have shown success, such as non-small cell lung cancer or bladder cancer.

Despite the challenges, iADCs are attracting significant investment. Mersana has partnerships with GSK and Merck KGaA, with potential deals worth billions of dollars. Sutro, backed by Astellas Pharma, stands to gain substantial milestone payments and royalties.

In summary, while iADCs represent a promising frontier in cancer treatment, they face significant technical and clinical hurdles. Continued research and investment may eventually lead to breakthroughs that offer hope for more effective and potentially curative cancer therapies.