Translating research into therapeutics: the future of ADCs in cancer therapy

You recently transitioned into your first industry role after spending your career in academic research. What motivated this shift, and how has your academic background influenced your current work?

Y-TT: My transition from academia to industry was driven by several key factors. First, I wanted to broaden my impact by contributing directly to biotech innovations. Industry is highly specialized in technological development, and working here allows me to play a more immediate role in advancing new products and therapies.

Second, resource availability and funding were considerations. In industry, projects are often better supported, whereas academia faces funding constraints despite having the benefit of research freedom. Third, I saw an opportunity for career growth. My experience at Dana-Farber exposed me to industry-academic collaborations aimed at translating biotech innovations into clinical applications. By moving into industry, I hope to bridge this gap and accelerate the development of novel therapeutics.

Work-life balance was also a factor, as industry roles tend to have more structured schedules. However, I remain committed to the competitive nature of this field, especially in areas such as ADCs.

My academic background brings a unique perspective to biotech, particularly in disease and target biology. By integrating this expertise with industry’s technological strengths, I aim to help accelerate the development of innovative drugs for patients with unmet medical needs. This transition marks an important milestone in my career, allowing me to merge academic insights with industry-driven innovation while continuing to learn and adapt.

ADCs and multiple myelomas (MM) are advancing rapidly. What factors are driving this progress, and what do you see as the next major milestone?

Y-TT: Currently, MM treatments have been heavily focused on bispecific T-cell therapies and CAR-T cell therapies. While bispecific antibodies may be off-the-shelf, ADCs are fully off-the-shelf therapies, requiring fewer logistical challenges. Looking ahead, the next generation of ADCs will likely be more personalized to enhance therapeutic efficacy and durability of response. Unlike CAR-T therapies, which require patient-specific manufacturing, ADCs offer broader accessibility, making them easier for cancer centers to implement.

Future advancements will continue to focus on targeted therapies, and ADCs align well with this approach. They reduce the non-specific toxicity associated with traditional chemotherapy while allowing for continued innovation in linker and payload technology. There is still significant room for improvement, leveraging discoveries from academic research to refine ADC design through medicinal chemistry, linker optimization, and payload development. These foundational studies will drive the next wave of ADC innovation.

A key goal is ensuring that newly developed ADCs succeed in clinical trials and ultimately receive regulatory approval to make them available to patients. Additionally, ADCs hold significant potential for combination therapies and not just in MM but also in solid tumors, which is my current area of focus. In myeloma, standard treatment already involves multiple drug combinations, and ADCs have characteristics that make them strong candidates for integration into these regimens. Their ability to function like small molecules while also inducing immune-mediated effects provides a compelling rationale for their inclusion in ‘treatment cocktails’. The goal is to enhance patient outcomes and quality of life, particularly for those who are severely ill or immunocompromised, as the ADCs do not require the patients to have an effective immune system.

If CAR-T and bispecific T-cell therapies have achieved such success, ADCs should also have a promising future. While challenges remain, ongoing advancements in ADC design, manufacturing, and clinical application suggest a bright future for this therapeutic approach.

Monomethyl auristatin F (MMAF) has shown specificity, cytotoxicity in in vitro studies, but it hasn’t yet led to an approved drug. What challenges remain and bringing this technology to clinical use?

Y-TT: My work with MMAF dates back to a publication in 2014. At the time, MMAF was a novel payload, following the development of monomethyl auristatin E (MMAE). Seattle Genetics—now part of Pfizer—pioneered both compounds, and early clinical trials demonstrated promising efficacy. However, despite this potential, MMAF, which induced even more specific anti-tumor effect than MMAE in MM, failed to gain FDA approval due to concerns about its ability to outperform the standard of care in clinical trials, as well as safety considerations.

Several challenges remain in bringing MMAF to clinical use, though significant progress has been made. One major issue identified during trials was ocular toxicity, an off-target effect that was not fully understood at the time. Over the years, through studies such as DREAMM-1, DREAMM-2, and now DREAMM-8, clinicians have developed better strategies for managing this toxicity, which has been a critical advancement.

Another challenge is drug delivery. To maximize therapeutic benefit while minimizing harm to healthy tissues, optimizing linker technology and antibody specificity is essential. Advances in delivery mechanisms could help ensure that MMAF reaches tumor cells more selectively, reducing off-target toxicity. Additionally, resistance mechanisms also pose a significant hurdle. Cancer cells continuously evolve, and one common resistance mechanism is the downregulation of target antigens, leading to reduced drug efficacy. Ongoing research is focused on understanding and overcoming these resistance pathways to enhance MMAF’s long-term effectiveness.

Clinical trial design is another key factor. Determining the optimal dosing schedule, treatment duration, and patient selection criteria is crucial for maximizing efficacy while minimizing side effects. Advances in AI and genomics now allow for more precise patient stratification, which could improve trial success rates compared to earlier studies. Further, regulatory hurdles play a role as gaining FDA approval requires rigorous testing and extensive documentation to meet safety and efficacy standards. Navigating this regulatory landscape efficiently is essential for bringing MMAF to market.

Moving forward, improving targeting strategies and reducing off-target toxicities—potentially through combination therapies—will be critical. Lowering the required drug concentration while maintaining efficacy could also help mitigate side effects. With ongoing advancements in clinical trial design and cancer biology, I am confident that MMAF has the potential to be revived as a viable treatment option for MM and solid tumors. Ensuring that clinicians have access to a broader range of therapeutic options will ultimately improve patient care and outcomes.

In your work with solid tumors, ADCs have shown more success compared to other immunotherapies. What makes ADCs a more promising approach for solid tumors?

Y-TT: ADCs have demonstrated significant success in solid tumors, largely due to our deep understanding of tumor biology and target antigens. For example, HER2 has been extensively studied, particularly in breast cancer, where high expression levels have made it a key therapeutic target. This foundational knowledge paved the way for the success of HER2-targeted therapies like Trastuzumab, Kadcyla (T-DM1), and Enhertu (T-DXd). Similarly, while EGFR-targeted therapies have been more effective with small molecules, ADCs targeting HER2 and other well-characterized antigens have shown great promise.

One critical factor contributing to ADC efficacy is target specificity. The antibodies used in ADCs can induce strong internalization upon binding, ensuring efficient drug delivery into cancer cells. While internalization remains a key mechanism for ADC function, newer technologies are emerging that allow ADCs to be effective even when internalization rates are lower. These advancements are expanding ADC applicability and driving further innovation.

Another important consideration in solid tumors is antigen heterogeneity. Unlike hematologic malignancies, where target expressions are often uniform, solid tumors exhibit heterogeneous antigen expression. This makes the bystander effect a key factor in ADC success. Achieving an optimal bystander effect can enhance ADC efficacy, particularly in bulky, tissue-based tumors where drug penetration is a challenge.

ADCs also offer a significant advantage over traditional chemotherapy by reducing systemic toxicity. Their targeted approach aligns with the early vision of monoclonal antibodies as ‘magic bullets’ capable of delivering treatment directly to cancer cells without harming healthy ones. Further, ADCs have demonstrated synergy with standard chemotherapy and immunotherapy. Beyond their direct cytotoxic effects, ADCs can modulate the immune system, enhancing anti-tumor immune responses. The success of ADCs such as T-DM1 (Kadcyla), T-DXd (Enhertu), and TROP2-targeting ADCs further reinforces their potential. The recent FDA approvals of new ADCs highlight their growing role in cancer treatment, providing potent and effective options with manageable toxicity profiles.

Ultimately, ADCs represent a promising approach for solid tumors, and continued advancements in linker technology, payload optimization, and drug penetration strategies will further enhance their clinical impact.

Ten years ago, you published a paper that focused on the therapeutic use of ADCs in MM, however, there were only a handful of clinical trials at that time. What has surprised you most about how the field has evolved since then?

Y-TT: One of the most notable developments has been the evolution of B-cell maturation antigen (BCMA)-targeting ADCs, particularly belantamab mafodotin (Blenrep). As previously mentioned, ocular toxicity has been a distinct challenge with MMAF-based ADCs, and belantamab remains the only MMAF payload ADC in myeloma to date. The drug was withdrawn from the market around 2022 following the results of the DREAMM-3 trial. However, the field has made significant progress in understanding how to better manage its side effects, and the latest DREAMM-8 trial results suggest renewed optimism.

A key learning from DREAMM-8 has been the ability to achieve comparable, or even improved, progression-free survival by adjusting dosing strategies. By reducing the drug concentration and extending the treatment cycle from three weeks to four weeks, researchers have found a way to maintain efficacy while improving the safety profile. These findings, presented at the American Society of Hematology Annual Meeting and discussed among leading clinicians, have fueled hopes of reintroducing belantamab to the market.

Looking ahead, once the challenges surrounding MMAF toxicity are addressed, there is strong interest in moving BCMA-targeting ADCs into earlier lines of treatment. The DREAMM-8 trial, which investigated belantamab (B) in combination with pomalidomide and dexamethasone (PD) —both standard-of-care agents— showed promising safety and efficacy results when compared to Velcade (bortezomib) combination (VPD). Given Velcade’s pivotal role as the first proteasome inhibitor in MM treatment, seeing ADCs demonstrate comparable or improved outcomes is highly encouraging. This progress suggests that ADCs could soon be incorporated into earlier treatment settings, even following initial diagnosis.

In terms of future directions, personalization of ADC therapy is an exciting area of research. Technologies such as single-cell sequencing could help refine patient selection and optimize ADC treatment strategies. Additionally, novel payloads are emerging as potential alternatives to MMAF. For example, Heidelberg Pharma has developed a payload that inhibits protein translation, offering a distinct mechanism of action from traditional MMAF-based ADCs. This approach has shown promising results in Phase 1 trials, and another company has already developed a similar candidate with encouraging in vitro data.

Lastly, what do you hope will be the key breakthroughs in ADC fields over the next few years, specifically in overcoming challenges with off-target toxicity and resistance?

Y-TT: One of the most critical challenges in ADC development, as mentioned, is preventing resistance. A common mechanism of resistance is the downregulation of target antigens, which reduces the drug’s effectiveness. To address this, bispecific ADCs could offer a promising solution. Not only would this enhance tumor specificity, but it could also mitigate resistance by ensuring that the drug remains effective even if one target is downregulated.

Several clinical trials are already exploring bispecific ADCs, including those targeting prostate cancer and EGFR. The key challenge will be identifying the most effective antigen combinations, leveraging existing platforms such as HER2 and TROP2 as backbones while incorporating additional tumor-specific targets.

Additionally, an area of advancement that will hopefully see a breakthrough is the linker and payload technology. The stability of ADCs in circulation remains a challenge as premature payload release can contribute to off-target toxicity. Future research should focus on developing highly stable linkers that ensure payload release occurs exclusively within tumor cells. This could also lead to more homogenous ADCs, optimizing drug-to-antibody ratios for improved efficacy and reduced toxicity.

In terms of enhancing ADC effectiveness, combination therapies will play an essential role. In addition to the emerging class of protein translation inhibitors, researchers are now exploring immunomodulatory ADCs. For example, the STING pathway has been identified as a potential target for ADC payloads. STING agonists can activate the immune system, potentially creating a dual mechanism of action where ADCs not only kill tumor cells directly but also stimulate an immune response for a more sustained anti-tumor effect.

Personalized medicine will also be fundamental in refining ADC therapies. Biomarker-driven research can help identify which patients will benefit most from specific ADCs. For example, differentiating between HER2 and EGFR expression levels can guide treatment selection, ensuring that ADCs are used in the most responsive patient populations. Additionally, advancements in single cell sequencing and AI are already being utilized by major pharmaceutical companies to optimize target selection. AI and machine learning can help analyze vast datasets, pinpoint specific patient subsets, and refine clinical trial designs to develop more precise and effective ADC-based therapies.

Biography

Yu-Tzu Tai joined Oxford Biotherapeutics in 2022, bringing expertise in cancer and immune oncology research. Her translational work has led to FDA-approved therapies including small molecules (BTK, XPO1, IMiDs, PIs) and biologics (CD38, SLAMF7, BCMA). Tai has authored over 210 scientific articles and spent 25 years at Dana-Farber Cancer Institute, holding patent publications. She is a long-term member of AACR and actively serves on the editorial board of Clinical Cancer Research. At Oxford Biotherapeutics, she oversees ADC programs and preclinical studies for ongoing OBT076 trials while supporting external partnerships, all aimed at developing innovative immunotherapies for unmet medical need.

Affiliation

Yu-Tzu Tai PhD, Associate Director, ADC and Translational Research, Oxford Therapeutics, Inc., San Jose, CA, USA

Authorship & Conflict of Interest

Contributions: The named author takes responsibility for the integrity of the work as a whole, and has given his approval for this version to be published.

Acknowledgements: None.

Disclosure and potential conflicts of interest: The author has no conflicts of interest.

Funding declaration: The author received no financial support for the research, authorship and/or publication of this article.

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Attribution: Copyright © 2025 Oxford BioTherapeutics. Published by Bioconjugation Insights under Creative Commons License Deed CC BY NC ND 4.0.

Article source: Invited.

Revised manuscript received: Apr 15, 2025.

Publication date: Apr 25, 2025.