Finding protein therapeutics for cancer treatment

The American Association of Cancer Research (AACR) Annual Meeting took place from 5-10 April 2024 in San Diego. DDW’s Megan Thomas spoke with Dr Paul Moore, Chief Scientific Officer at Zymeworks and Dr Nina Weisser, Director of Multispecific Antibody Therapeutics at Zymeworks, about the event as well as the future of cancer research. MT: Can you give a topline summary of the new data presented at AACR? We had five presentations at AACR this year providing new details on Zymeworks’ preclinical pipeline, including an update on ZW191, our FRa targeted ADC which we anticipate filing an IND application on this year, and progress on one of our trispecific T cell engager (TCE) platforms. Collectively, the data presented highlighted the strength of the company’s preclinical pipeline and our potential to develop novel antibody-drug conjugates (ADCs) and multispecific antibody therapeutics (MSATs) using complementary, antibody-based technologies. Our MSAT presentations focused on our TriTCE Co-Stim platform, a next generation T cell engager with integrated CD28 costimulation. We presented data on the platform itself and in the context of two tumour targeting antigens (CLDN18.2 and DLL-3), highlighting enhanced mechanistic and anti-tumour activity compared to clinical benchmark CD3 bispecifics targeting the same antigens. We believe this advancement will provide a potential therapeutic modality to treat tumours with limited tumoural T cell infiltration and poor T cell function that are underserved by existing immune based therapies. The ZW191 presentation included new data demonstrating the superior internalisation, payload delivery and spheroid penetration of the parental FRa antibody incorporated in ZW191 compared to other FRα-targeted antibodies being developed as ADCs. Expanded preclinical anti-tumour activity of ZW191 across multiple FRa expressing tumour types including ovarian, lung, endometrial, and triple-negative breast cancer (TNBC) was also presented, in addition to repeat dose safety studies in non-human primates (NHP) demonstrating its favourable tolerability profile. Beyond the ZW191 poster, our ADC team also presented on the development of novel 3D cancer cell model systems, that are more predictive of in vivo anti-tumour efficacy in xenograft and PDX models, that support functional screening and characterisation of our ADC molecules. Finally, we shared progress made on combining our expertise in multispecifics and ADCs in the development and screening of a library of bispecific ADCs. Specifically in the generation and screening of a library of bispecific ADCs, to identify those optimally formatted to overcome challenges associated with targeting a single antigen. Overall, the presented data highlighted the attention to design and functionality of our multispecific and ADC platforms, that is also reflected in the favourable preclinical profile of our molecules to benchmark comparators. Importantly we believe the approaches shared can also be extended to additional cancer types and associated targets. MT: How will these developments influence the landscape of the development space for antibody drug conjugates (ADCs) and T cell engagers (TCEs)? Our team’s goal is to develop a diverse pipeline of novel therapeutics that can improve the standard of care for cancers and other diseases that are currently labeled as “difficult-to-treat.” In the ADC treatment space, we chose to develop therapeutic candidates that have the potential to address challenges associated with the existing ADC treatment space, including high discontinuation rates, off-target toxicities and issues related to maximum tolerated doses. In the T cell engager treatment space, we are focused on developing therapeutic candidates that have the potential to overcome challenges that have plagued TCE treatment, including limited success against solid tumours as a result of a narrow therapeutic window due to dose-limiting toxicities associated with cytokine release syndrome (CRS), neurotoxicity, on-target-off-tumour effects or poor anti-tumour activity. MT: What are some key takeaways from your time at AACR Progress was reported across all aspects of oncology, from basic biology to clinical studies with informative updates on various therapeutic modalities, including targeted small molecules, immune and cellular therapies, and cancer vaccines. As researchers dig deeper into cancer mechanisms at the cellular level, both within the tumour microenvironment and the host macroenvironment, the level of complexity and multitude of factors controlling tumour growth and metastases is becoming more apparent, albeit still not fully understood. Importantly, the various deep-data multi-omics approaches being applied across the spectrum of tumour types are being paced with advances in computational biology and artificial intelligence (AI) that should accelerate our understanding of the data and contribution of various pathways. This is already yielding new insights to molecular targets and cellular mechanisms to leverage in the design of next generation cancer therapeutics. While there has been remarkable progress in the last 5-10 years with immune based therapeutics including checkpoint inhibitors, CAR-T cells and antibody-drug conjugates, results from clinical trials presented at the meeting clearly show the need for further advancements, to increase the breadth of patients that respond, to improve the depth of responses, to limit side effects and to better select patients that will benefit from particular treatment regimens. MT: What do you think is the most exciting opportunity for global cancer research? With increasing knowledge of the fundamental pathways and mechanisms driving cancer, and learnings from existing cancer therapeutics – both approved and in development – the opportunity to build next generation multi-functional therapeutics that incorporate these learnings into their design is here. The critical cancer signaling pathways to either block or leverage, the cell populations to eradicate or mobilise, and the targets to select for those populations are becoming increasingly apparent from deep profiling and advancements in tools to interpret. Advances in AI to drive more rapid and effective design of therapeutics to leverage this knowledge should translate into better therapeutics, while advances in individual patient profiling should aid in patient selection. The ability to also combine multiple mechanisms of action into a single multi-functional therapeutic layered with therapeutic combination strategies should further advance benefit to cancer patients across the globe. MT: Where are the challenges in cancer research and how is the work Zymeworks is doing going to influence them? Two challenges that Zymeworks is focused on addressing include challenges associated with the biology of the tumour that play a role in treatment resistance and failure, and challenges associated with the optimisation of drug design that maximise the therapeutic window to enable delivery of safe and effective therapies. Both the biology of the tumour and tailored drug design are considered in the development of our ADC and multispecific therapies. For example, biological challenges associated with tumour heterogeneity – which is thought to limit treatment responses and drive resistance – is being address with the design of our bispecific ADCs that can target two different tumour targets both simultaneously and independently may overcome challenges associated with target heterogeneity and the reliance on target co-expression associated with bivalent bispecific antibodies. Additionally, biological limitations associated with tumours with poor immune function are being address with our trispecific TriTCE Co-Stim molecules that provide balanced and target-dependent T cell activation of both Signal 1 (through CD3) and Signal 2 (through CD28) in a single molecule. TriTCE Co-Stim have the potential to induce more sustainable T cell responses in the tumour microenvironment to treat tumours with low T cell infiltration and poor T cell function that are under-served by existing immune based therapies. In terms of challenges associated with optimising drug design, both our ADC and multispecific candidates build on the learning within the field and employ tailored engineering of each molecule component to maximise the therapeutic benefit to patients. With ADC-based treatments, our team is focused on addressing a number of ADC associated challenges including high discontinuation rates, maximum tolerated doses and severe off-tumour toxicities such as nausea, anaemia, interstitial lung disease, neutropenia, and gastrointestinal effects. We have seen in emerging clinical data that treatment-related off-target toxicities and maximum tolerated doses are primarily related to ADC payloads while the efficacy of ADC-based treatments is likely driven by a combination of targeted payload delivery, free payload exposure and tumour sensitivity to the molecule’s components. With these insights in mind, our candidates are chosen and developed while keeping all properties of the ADC in mind, including the target, antibody, linker and payload. This approach allows us to maximise the clinical efficacy of a candidate while balancing the risk of off-tumour toxicity. By coordinating the design of ADC candidates, our hope is to provide unprecedented clinical benefit to patients and afford them the best possible chance of a positive outcome. Similarly, with our T cell engaging-based multispecific treatments, our team is focused on addressing design limitations associated with TCE. TCE have exhibited clinical utility against haematological malignancies but have shown limited success against solid tumours as a result of a narrow therapeutic window due to dose-limiting toxicities associated with CRS, neurotoxicity, on-target-off-tumour effects or poor anti-tumour activity. Our team is addressing these limitations through the optimisation of paratope affinities including low affinity binding to CD3 and CD28 to reduce cytokine release, and antibody format and geometry engineering to drive tumour selective binding and activity to limit on-target-off-tumour effects and enhanced anti-tumour activity. Biographies Dr Paul Moore is Chief Scientific Officer at Zymeworks. He has more than 25 years of US-based experience in biologics drug discovery and development in biotechnology research. His career efforts have led to the discovery and development of a range of FDA-approved and clinical-stage biologics for patients with difficult-to-treat cancers and autoimmune conditions. Dr Moore received a PhD in molecular genetics from the University of Glasgow. He has an extensive research record, co-authoring more than 75 peer-reviewed manuscripts and is a named co-inventor on over 50 issued US patents. Dr Nina Weisser is the Director of Multispecific Antibody Therapeutics at Zymeworks. She has more than 20 years of experience in biologics and antibody engineering and has spent more than 12 years on the Zymeworks multispecific antibody team, where she now leads the preclinical programmes group and plays a key role in the development of the company’s lead clinical candidates and preclinical research programmes. Dr Weisser received a PhD in antibody engineering from the University of Guelph.