ADC Therapeutics, Sutro Biopharma and Zai Lab are among those developing antibody-drug conjugates to address payload and toxicity challenges of current ADCs—and rapidly grow the multi-billion-dollar market.
Though antibody-drug conjugates are not new, advancements in payload and linker technologies are helping to make ADCs a rapidly growing therapeutic class within the cancer space. Valued at just over $12 billion in 2024, the global market for ADCs is projected to reach $44 billion by 2029.
Combining the specificity of monoclonal antibodies with the potency of cytotoxic drugs, ADCs are designed to target and kill cancerous cells with the potential to significantly improve the outcomes of current cancer therapies such as chemotherapy. Arguably one of the hottest emergent areas in oncology, next-generation ADCs are striving to overcome toxicities and payload challenges and could be used to treat evasive solid tumors.
In an opinion piece for BioSpace, Zymeworks Chief Scientific Officer Paul Moore wrote that ADCs have now entered their “golden age”, with companies working to overcome the current limitations of the technologies.
Zai Lab Competitive With Amgen in Lung Cancer
One of those companies is Zai Lab, which claims to have a novel linker-payload platform—via MediLink Therapeutics’ proprietary TMALIN—that leverages the tumor microenvironment to reduce off-target payload toxicity.
“The old generation [of ADCs] had no control of the number of payloads . . . and they had no control on how many of these molecules will be released,” Rafael Amado, president and head of global research and development at Zai Lab, told BioSpace. “Now we can fix the [drug-to-antibody ratio]. We can use artificial amino acids to put them exactly where we want in the antibody and we can make them be released in the right compartment, thereby minimizing toxicity.” Amado noted that an ongoing “renaissance” in ADCs is “due to the fact that the very narrow therapeutic window that existed before has now widened.”
Zai Lab’s investigational next-generation ADC ZL-1310 is composed of a humanized anti-DLL3 monoclonal antibody linked to a novel camptothecin derivative (a topoisomerase 1 inhibitor) as its payload. DLL3 is an inhibitor of the Notch ligand that is overexpressed in small cell lung cancer (SCLC) and neuroendocrine tumors.
At the ENA Symposium in October, Zai Lab presented data from a Phase I study of ZL-1310, which suggest the next-generation ADC has the potential to deliver a robust anti-tumor response while minimizing toxicity in individuals with relapsed or refractory SCLC.
The objective response rate was 74% for ZL-1310 in extensive-stage SCLC patients with at least one post-treatment evaluation, with anti-tumor activity demonstrated across all dose levels. In terms of safety, the ADC was well tolerated with the majority of treatment emergent adverse events being Grade 1 or 2.
Jefferies analyst Michael Yee in an Oct. 24 note to investors called the early-stage results “very promising” and said they show “a strong and differentiated efficacy and safety profile” compared to Amgen’s bispecific T cell engager molecule tarlatamab which was granted FDA accelerated approval in May for extensive-stage SCLC.
“It’s early so we will have to see what the numbers are with more patients,” Amado said.
Comprehensive Optimization
While Sutro Biopharma may be best known for luvelta, a folate receptor-α-targeting ADC in Phase III development for ovarian cancer and earlier stages for other tumors, the company is also working on next-generation ADCs designed to mitigate toxicity risk, improve efficacy and broaden the addressable patient population. Its early-stage pipeline includes dual-payload and immunostimulatory ADCs.
According to Sutro CEO Bill Newell, currently only about 1% of the ADC dose gets into the tumor, “so the other 99% has the opportunity to create a lot of side effects that are undesirable.” Sutro is designing its molecules to be able to deliver a higher drug-to-antibody ratio (DAR) than first-generation ADCs and to minimize toxicities. Noting several toxicities that have been identified over the past decade or so, Newell said, “we can manipulate the design to avoid those toxicities.”
Sutro held a research forum in October highlighting the company’s pipeline of next-generation ADCs, with plans to bring three new assets to the clinic over the next three years. These include the tissue factor-targeting ADC STRO-004, which uses linker-warhead technology at a high enough DAR to create more potent in-tumor killing, Newell said.
“The linker is probably the most stable linker that we’ve seen and the warhead—with a drug-to-antibody ratio of eight—is probably the most potent that you will be seeing from companies that are trying to do this type of molecule,” Newell said. Sutro’s goal is to get to a DAR of 12 “without increasing toxicity materially.”
STRO-004, which Sutro contends has “broad, pan-tumor potential,” features a DAR of 8 with its exatecan payload and site-specific linker. The asset has demonstrated greater anti-tumor activity and lower toxicities than a tissue factor benchmark ADC in preclinical models. The company expects to file an IND for STRO-004 with the FDA in the second half of 2025.
Newell credits Sutro’s proprietary cell-free XpressCF platform with enabling the precise design of ADCs with a wide range of features that he contends are not possible with other platforms. It’s a value proposition that appears to have won over Truist Securities analyst Asthika Goonewardene.
“While many in the ADC field are merely making incremental adjustments or fine-tuning one component of the ADC, we applaud Sutro for developing a platform where essentially all components of the ADC can be engineered and optimized,” Goonewardene wrote in an Oct. 20 note to investors.
Goonewardene said that while near-term investor focus is on luvelta, his firm is “optimistic” that Sutro’s platform “will differentiate it as a company.”
Potent Payloads
Meanwhile, ADC Therapeutics is focused on advancing next-gen ADCs for the treatment of hematologic cancers and solid tumors. The company’s proprietary pyrrolobenzodiazepine (PBD) dimer technology is being leveraged to develop DNA cross-linking warheads to elude DNA repair/cancer resistance mechanisms.
PBD-based drugs are ADCs that recognize proteins like CD19 or CD22 to deliver chemotherapy directly to targeted cells, reducing side effects. ADC Therapeutics’ Zynlonta, a CD19-directed ADC, was granted accelerated approval by the FDA in 2021 for adult patients with relapsed or refractory large B cell lymphoma after two or more lines of systemic therapy.
Bound to a CD19-expressing cell, Zynlonta is internalized by the cell and the PBD payload is released to bind the DNA double helix’s backbone, where it remains less visible to DNA repair machinery and ultimately results in cell cycle arrest and tumor cell death.
ADC Therapeutics CEO Ameet Mallik told BioSpace that Zynlonta—the company’s only approved product—has a unique and very potent PBD payload. “If you look at most ADC payloads, they’re about 10 times more potent than chemotherapy. PBDs are 10 times more potent than other ADC payloads,” Mallik said.
At the same time, Mallik acknowledged that there are advantages and disadvantages to having the most potent payload. “When you’re working with potency, you really need a strong linker system that can help deliver it,” he said—so you don’t “have a lot of dispersion of the molecule before it gets into the cell.” Mallik credited ADC Therapeutics’ linker technology for its regulatory approval as it created “stability to have our conjugate in the PBD to have it really internalized in the cell.”
Mallik said that ADC Therapeutics was the only company with an approved PBD-based product and acknowledged that, so far, PBD toxins haven’t proven particularly successful in solid tumors. “We’ve seen good efficacy in hematology,” he said, but “the jury is still out” when it comes to solid tumors.
Jefferies analyst Kelly Shi in a Nov. 7 note to investors highlighted the fact that Zynlonta boasts a “potent DNA cross-linking warhead, serving as validation for subsequent pipeline assets.” She added that the company’s strategy “could allow Zynlonta to become a backbone therapy in [second line] DLBCL w/ different combination options.”
Beyond Oncology
For now, ADC Therapeutics is focusing on cancer. However, Mallik sees the potential to leverage ADCs for autoimmune diseases. “The drugs that get conjugated are likely to be different, because one of the things you see in oncology is you’re not only trying to get cell-killing, you’re trying to get bystander effect,” where treated cancer cells inhibit the growth of their untreated neighbors, he said. “For autoimmune, it’s a little bit different where you actually don’t want that bystander effect.”
Amado agreed that ADCs can be used to deliver not just toxic payloads but other molecules as well. “They don’t all need to be antibodies. They could be fragments, large molecules, polymers and specific inhibitors,” he said. “It will take some time, but I have no doubt that [ADCs] will make it as a modality in other therapeutic areas.”
