Trastuzumab-QYYP(Pfizer Inc.)

Pictured: A white blood cell charging an ADC/Taylor Tieden for BioSpace The antibody drug conjugate market is one of the fastest growing in the pharmaceutical industry, expanding from $1 billion to $10 billion in yearly sales between 2015 to 2023—and expected to rise to $28 billion by 2028, according to Evaluate. But despite their high level of efficacy in delivering cytotoxic payloads directly to tumor cells, antibody-drug conjugates (ADCs) are “unfortunately not curing people,” Tim Lowinger, senior vice president and chief science and technology officer at Mersana Therapeutics, told BioSpace. There are real benefits, he said, including prolonged life and extended progression-free survival, yet reemergence occurs. With 15 ADCs approved as of February 2024 and many more in company pipelines, drug developers are expanding their focus to ask how they can build on the success of ADCs. Enter immunostimulatory ADCs (iADCs), sometimes called immune-stimulating antibody conjugates (iSACs). Immunotherapies are already proven cancer drugs, and delivering these treatments via ADC offers the potential to precisely target tumor cells while protecting normal cells, said Jane Chung, president and chief operating officer at Sutro Biopharma. “Engineering very targeted therapies so that you can dial up the potency of whatever payload you’re using, that’s going to . . . really move the needle on advancing cancer care,” Chung told BioSpace. Hitting the Gas on Immune Response The excitement around iADCs stems from the success of checkpoint inhibitors, said Nathan Tumey, an associate professor at Binghamton University’s School of Pharmacy and Pharmaceutical Sciences. Tumey told BioSpace that checkpoint inhibitors essentially take the brakes off of the immune system, enabling it to attack cancer cells. iADCs offer the potential to take this further and “step on the gas,” ramping up the immune response. Some of the cytotoxic payloads carried by current ADCs are also known to cause immunostimulatory cell death by creating more neoantigens in the tumor, Lowinger explained, driving companies like Pfizer to combine its auristatin-based ADC with a checkpoint inhibitor for a synergistic effect. For Lowinger, this aspect raises the question: “If a secondary mechanism of immunostimulatory cell death can have a benefit, what if you made this your primary mechanism of action?” That idea is driving interest now in iADCs. Biopharma companies are targeting a number of pathways to activate the innate immune system. Mersana, for example, is developing a stimulator of interferon genes (STING) agonist. While STING activation has known anti-cancer effects, it’s been a historically difficult target because activating it throughout the body can be toxic. The drug needs to be activated only once bound to tumor cells—which is precisely what ADCs were made to do. Using its immunosynthen platform, Mersana designed its STING agonist to stay put once delivered inside the cell with a stable, cleavable linker scaffold. Its lead asset is currently in Phase I trials against multiple HER2-positive solid tumor types. Instead of using the monoclonal antibody trastuzumab often paired with current HER2-targeting ADCs, Mersana developed a novel antibody. Therefore, it could potentially be used in combination with established, cytotoxic ADCs, as the two would not be competing for the same binding site. Meanwhile, Burlingame, CA–based Tallac Therapeutics has TAC-001, a TLR9 agonist ADC in a Phase I/II trial for solid tumors. While most ADCs carry small molecule payloads, Tallac’s platform can conjugate an oligonucleotide to an antibody, allowing modalities beyond cytotoxicity, Hong Wan, CEO of Tallac, told BioSpace. Because TLR9 is part of the innate immune system and expressed near-exclusively on immune cells, it has potential for a durable response via “immune memory,” in addition to increased safety and tolerability, Wan said. Wan pointed to the high toxicity of many current ADCs and the very high target protein expression required in the tumor to elicit the cytotoxic effect, which can restrict the efficacy to a limited patient population. In contrast, iADCs don’t require very high target expression, she said, so they could potentially benefit a broader patient population. Though data from a Phase I/II dose escalation trial have not yet been disclosed, Wan indicated the company has seen a positive response to TAC-001 in melanoma. The candidate has also been studied in the preclinical setting alongside a cancer vaccine, with positive results shared in April. And it has been combined with multiple chemotherapies preclinically. Next, Tallac is planning to test the candidate in combination with a PD1 checkpoint inhibitor. In a twist on the combination approach, South San Francisco’s Sutro—in partnership with Astellas—is taking a dual conjugation approach with its iADC. “When we put both elements, the chemotherapy and the PD1 immune activator, on an antibody . . . we reduce the tumor volume and activate the immune system to get rid of the remaining tumor cells,” said Hans-Peter Gerber, chief scientific officer at Sutro. Balancing ratios between the two elements can be precarious and the technology is critical, Gerber told BioSpace, adding that he believes Sutro stands alone in being able to dial in the correct balance. While the Astellas-partnered program does not yet have a disclosed target, Gerber said the obvious strategy would be to start in indications where immune checkpoint inhibitors already work, such as melanoma and lung and kidney cancers, then expand to populations that cannot benefit from a checkpoint inhibitor. Colorectal cancer is a “bold goal” for the company, he added. A Difficult Path The path has not been a smooth one for iADCs, though. Thanks to some highly visible clinical failures, “the field has a bad rap,” Tumey said. In 2022, an iADC combining an anti-HER2 MAB with a TLR8 agonist failed. Its developer, Silverback Therapeutics, ceased operations and became a shell company for a reverse merger with a different biotech. Two years later, Bolt Therapeutics had essentially the same results for a similar treatment. A HER2-targeting iSAC developed by Novartis also failed a Phase I trial for non-breast malignancies in 2021. “This remains a challenging area for drug discovery with considerable technical risk, as the common targets such as TLR-7, -8, -9 and STING have not yet been successfully drugged with any type of therapy,” Dan Chancellor, vice president of thought leadership at pharma solutions provider Norstella, told BioSpace in an email. He added that the iADC technology is in the beginning stages of development. However, the aforementioned three failures really amount to one, Tumey said. The companies were doing essentially the same thing—using non-cleavable linkers and effector function ADCs targeting HER2—so if one failed, “of course they’re all going to fail.” Additionally, “I think maybe a mistake that the field made early on was trying to go after breast cancer,” he said. While it seemed like the lowest hanging fruit, it’s difficult because it is an immunologically cold tumor. Like Gerber, Tumey said he believes iADCs have the highest potential in areas checkpoint inhibitors have been most successful, like non-small cell lung cancer or bladder cancer. Thanks to the success on the cytotoxic side of the ADC space, Tumey said companies appear to be more willing to take risks, potentially opening the field for meaningful success. iADCs in the Limelight In a notoriously tough biopharma funding climate, iADCs are one area drawing investment from companies. Mersana, for example, has partnerships with both GSK and Merck KGaA. The GSK deal, worth up to $1.4 billion, involves a HER2-targeted iADC currently in a Phase I dose-escalation trial. In 2022, Merck KGaA dropped $30 million up front with another $800 million on the line to conjugate Mersana’s preclinical STING-agonist to Merck KgaA’s proprietary antibodies for up to two targets. Additionally, Astellas Pharma has invested $90 million up front with Sutro to develop iADCs for three targets. Sutro could receive an additional $422.5 million in milestone payments, plus royalties. Lowinger shared the story of a study Mersana conducted treating tumors in mice with the company’s STING iADC: their tumors disappeared. Mersana then rechallenged the mice, and in mice treated with an iADC, tumors would not regrow. “This allows for the hope and dream that there’s a chance to cure patients,” Lowinger said. “I think that’s the big differentiator and why there’s interest in this approach.” Kate Goodwin is a freelance life science writer based in Des Moines, Iowa. She can be reached at kate.goodwin@biospace.com and on LinkedIn.