Beyond the ADC Hype: Innovation is accelerating through bispecifics and dual payload strategies
Antibody drug conjugates (ADCs) mark a new era in targeted cancer therapy, delivering potent cytotoxic chemotherapy via monoclonal antibodies directly into the tumor cells — an era with potentially new standard-of-care therapies without systemic chemotherapy and its associated side-effects for cancer patients.
Since approval of the first ADC Mylotarg® in 2000, 15 ADCs have been approved and 3 obtained Breakthrough Therapy Designation in 2025 alone. Now, the ADC market is poised for significant expansion, expected at $31B by 2030, reflecting a shift towards even more effective therapeutic options.
Medical community enthusiasm and confidence in the success of next-gen ADCs is high enough that top pharmaceutical companies are expanding their ADC pipelines either via M&A or licensing deals, such as AbbVie’s acquisition of Immunogen in 2024 or Merck Sharp & Dohme’s licensing agreement with Daiichi Sankyo in 2023.
The need for improvement persists—and with it, the imperative to innovate
Currently approved ADCs are associated with severe toxicities, including adverse events affecting the lungs, eyes and skin. Treatment resistance and tumor heterogeneity can also compromise the efficacy of those therapies. It has been shown that several mechanisms of resistance exist, from target downregulation, target mutation, to changes in internalization rates. Payload resistance is an additional growing issue that clinicians must face, as today approximately 45% of clinical-stage ADCs have a Topo1 payload class.
Optimization opportunities are truly multifaceted with improvements possible for the target, linker, conjugation method, payload MOA and carrier. Emerging approaches such as bispecific antibodies and dual-payload ADCs are opening new avenues to address heterogeneity and resistance.
Indeed, for these targeted therapies to achieve optimal efficacy, they must bind to cancer cells with optimal specificity and affinity. However, tumors are typically heterogeneous — meaning not all cells express the target receptor at the same level, and some may lack it entirely or become resistant by losing expression following specific treatment. This variability affects how well targeted molecules work in a certain population.
“If you target two receptors, you diminish the selection effectof cells that can escape the ADC killing” said Leo Marx, Debiopharm’s Head of ADC Research and Technologies. “This is one aspect where bispecific antibodies could make a difference - the second binding site can compensate if one receptor is not expressed, helping eradicate more tumor cells while sparing healthy tissue.”
Dual payload ADCs also address the resistance challenge. “What we’ve seen in our research is that 10 to 50% of cancer cells do not respond to a given cytotoxin, and there is no biomarker to select which patients would respond to one type of toxin or the other,” said Marx. “By combining them, we can increase the percentage of cancer cells that respond to ADCs and overcome resistance.”
Dual payload ADCs must be designed with even more emphasis on sparing healthy cells, as they may also express the target antigen at some level. “The goal is to avoid an additive effect on the toxicity profile,” said Marx. Optimizing drug delivery via linker chemistry and conjugation strategies is also a way to mitigate on- and off-target toxicity. All these developments hold the promise to ultimately increase ADC efficacy and therapeutic index.
Driving Innovation to Deliver More for Patients
“Targeted therapy options are limited for patients battling tumor types such as colorectal, pancreatic and certain rare cancers, underscoring a critical need for new treatment strategies”, said Sophie Brachet, Head of Early Commercial and Access for Debiopharm. “There are therefore unexplored opportunities to improve patient outcomes in new indications, and in tumor types where ADCs are already established, they are moving earlier in the treatment paradigm and increasingly used in combination regimens. However, sequencing ADCs is becoming a growing challenge, as many ADCs share the same payload — Topo1 inhibitors — raising concerns about cross-resistance.”
Oncologists are indeed introducing ADCs earlier lines of treatments in selected indications. Enfortumab vedotin (EV), approved in 2023 to treat advanced urothelial carcinoma, has become a new standard of care in first-line treatment in combination with pembrolizumab. Previously, advanced bladder cancer was typically treated with platinum-based chemotherapy, with serious side effects and limited long-term benefits.
Advancing next-gen ADCs at Debiopharm
The most advanced program, Debio 1562M, a 1st-in-class CD37-targeted ADC, is being evaluated in a first-in-human trial (NCT06969430), to treat acute myeloid leukemia and myelodysplastic syndrome.
“Debio 1562M is our front running clinical-stage program, among a broad and well-balanced ADC pipeline. We aim to drive innovation with first-in-class ADCs and differentiated best-in-class ADCs—leveraging novel bispecific designs and dual cytotoxic payload strategies.” commented Brachet.
The pipeline encompasses HER3-based bispecific ADCs, including the promising HER3-HER2 pair, with alternative payloads to the Topo1 class or dual payloads. The Swiss-based team is also uncovering novel targets, identifying new antigens on cancer cells, especially those on hard-to-treat solid tumors.
The Swiss, oncology focused biotech has developed a proprietary technology, on which all their ADC programs are built. The MultiLINKTM Technology Suite encompasses a range of linkers and conjugation technologies which uniquely allow building of dual payload ADCs at elevated DAR without impacting aggregation and exposure. In preclinical models, the MLINK Duo ADCs demonstrated excellent activity and enabled the resistance observed in models treated only with single-payload ADCs to be overcome. Research is also on-going on synergistic and non-cytotoxic novel payload classes.
“MultiLINKTM linker technology is engineered with hydrophilic components to offset the toxicity caused by lipophilic payloads,” added Marx. “We’ve shown that even with dual payload constructs — for example, eight molecules of one drug combined with eight molecules of another on a single antibody — we maintain excellent PK and low clearance in preclinical models.”
“Our ultimate ambition is for these next-gen ADCs to further enhance patient outcomes, particularly overall survival. We strive to fulfill the promise of precision chemotherapy and achieve the goal of replacing traditional chemotherapy as the standard treatment for select cancers.” said Brachet.
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