Breakthrough drug candidates and cancer treatment innovations

Dr Paul Moore emphasises the significance of T cell-engaging bispecific antibodies, like ZW171, in treating solid cancer tumours by overcoming biological obstacles in the tumour microenvironment. With a commitment to advancing novel medicines and leveraging strategic partnerships, he provides valuable insights into their cutting-edge research and development efforts.

Summary of findings:

• Antibody-drug conjugate candidate ZW191 demonstrated strong responses across a range of FRα-expressing patient-derived xenograft (PDX) models with favourable pharmacokinetic and safety profiles
• Multispecific antibody therapeutic candidate ZW171 induced potent preferential killing of cancer cells and potential to mitigate risk of on-target off-tumour toxicity, peripheral T cell activation, and cytokine-release syndrome
• Antibody-drug conjugate candidate ZW251 exhibited desired target-mediated activity in vitro and robust anti-tumour activity in HCC PDX models and a favourable preclinical safety profile.

Can you tell us more about ZW191 and its potential as an FRα-targeting antibody-drug conjugate?

ZW191 is an antibody-drug conjugate (ADC) that is engineered to target folate receptor-⍺ (FR⍺), a protein that has limited expression in normal tissues but is often elevated on a variety of tumours including epithelial ovarian, endometrial, triple negative breast and lung adenocarcinoma. ZW191 is comprised of a novel fully humanised IgG1 antibody covalently conjugated to a novel topoisomerase 1 inhibitor ZD06519, a camptothecin derivative, via endogenous interchain cysteines with a drug-to-antibody ratio (DAR) of eight. Upon target binding and receptor-mediated internalisation of ZW191, intracellular release of bystander-active ZD06519 induces cell death of FRα-expressing cells and the neighbouring cells through bystander-mediated killing.

ZW191 has exhibited compelling antitumour activity in preclinical models that supports potential activity in targeting FRα-high/mid/low ovarian cancers. The ADC demonstrated strong responses in FRα-low expressing PDX models, indicating potential activity in other oncology indications with lower levels of FRα. It also displayed favourable pharmacokinetics (PK) and is well tolerated in non-human primates (NHP) at exposure levels above those projected to be efficacious.

What are the advantages of ZW171 over other mesothelin-targeting agents in terms of safety and efficacy?

Mesothelin (MSLN) is overexpressed in many cancer indications, including pancreatic, mesothelioma and ovarian. There is a high unmet medical need in this area because while other candidates have shown early signs of clinical activity, there is still a need for therapies with improved safety and efficacy profiles.

T cell engager (TCE) candidates have exhibited clinical utility against haematological malignancies but have shown limited success against solid tumours due to dose-limiting toxicities associated with cytokine release syndrome (CRS) and other on-target, off-tumour effects.

ZW171 was identified after the company generated a panel of MSLN-targeting TCEs with a variety of formats, geometries and paratope affinities; we discovered this bispecific antibody that demonstrated enhanced anti-tumour activity and safety. It mediates potent preferential killing of MSLN-overexpressing target cells but is designed to limit the risk of on-target, off-tumour activity and peripheral T cell activation and CRS. Further, ZW171 demonstrated strong anti-tumour activity in MSLN^high and MSLN^mid expressing solid tumour models but was well tolerated in NHP. Data suggests that this candidate could overcome the challenges facing other TCEs developed to treat solid tumours. It also supports the argument for developing ZW171 for the treatment of other MLSN-expressing solid tumours.

What is the potential benefit of ZW171 in treating mesothelin-expressing solid tumours compared to other MSLN-targeting agents?

The current generation of TCEs have had limited success in solid tumours, partly to immunosuppression in the tumour microenvironment and partly due to systemic cytokine release. We are aiming to develop next generation TCEs that can navigate and overcome this difficult biology (mitigate cytokine release to optimise the therapeutic window; adjust T cell infiltrations and T cell anergy; circumnavigate the hostile immunosuppressive microenvironment).

We have engineered the format based on learnings in CD3/MSLN space to design multiple components to move into the clinic. Using an azymetric platform, we profiled multiple options to determine optimal activity compared to others. We included a low-affinity novel anti-CD3 to support killing but minimise cytokine release.

What is the significance of ZW191 demonstrating strong responses in FRα-low expressing PDX models for the treatment of oncology indications with lower levels of FRα?

The Fra-targeting antibody incorporated in ZW191 was selected to support enhanced internalisation and tumour penetration, key characteristics the team focused on to target a wider range of cancers with high, mid and low levels of FRα-expression, upon conjugation to the Topo1i payload employed. The strong responses in FRα-low expressing PDX models support potential activity for other oncology indications with lower levels of FRα. ZW191 also displayed favourable pharmacokinetics (PK) and is well tolerated in non-human primates (NHP) at exposure levels above those projected to be efficacious.

Can you elaborate on the potential of T cell-engaging bispecific antibodies, such as ZW171, to treat solid tumours?

Differentiated treatment options are needed, as cancer is a diverse disease that varies across and within organs due to many factors such as genetics, epigenetic influence as well as treatments (lines & type therapy). No single therapeutic mode has cured all cancers, so diversification in research and treatment is warranted.

The tumour microenvironment is complex; as such we feel our T cell-engaging multispecifics are ideal to navigate the biological obstacles. Our T cell engagers can have a variety of formats to overcome the physical barriers induced by stromal cells in the extracellular matrix.

To treat solid tumours with TCEs we have the option to customise our multispecific’s avidity (as in ZW171), the possibility to augment with check point inhibition or co-stimulation via CD28 targeting, and finally customising with or without an additional masking possibility to navigate different TMEs while eliciting multiple mechanisms of action which are engineered within a single molecule.

How does Zymeworks plan to advance at least five novel medicines into clinical studies by 2027 under its ZYME 5×5 R&D objectives?

We continue our in-house development strategy of accelerating our time from preclinical development candidate selection through IND filing. As such, our team remains on track to complete our 5×5 strategy – laid out in October 2022 – by harnessing our technology and resources to continue efficiently growing Zymeworks’ pipeline of in-house and partnered candidates. In 2024, we plan to advance ZW191 and ZW171 to the IND stage. We have multiple candidates undergoing preclinical evaluation including ZW251 and ZW220 (both Topo1i-based ADCs) in addition to next-generation T cell engagers that we anticipate providing additional IND molecules to enable our 5×5 strategy.

We are engaged in multiple collaborative efforts including our most recent partnership agreement with Jazz Pharmaceuticals, which will help fund and expedite the development of these and additional programmes, while leveraging non-dilutive funding mechanisms.

Author Bio:

Paul Moore, PhD

Dr Moore joined Zymeworks in July 2022 as Chief Scientific Officer. He brings over 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. Prior to joining Zymeworks, Paul served as Vice President, Cell Biology, and Immunology at MacroGenics, where he worked on the development of numerous clinical stage compounds and scientific collaborations with a range of pharmaceutical partners. Prior to joining MacroGenics, he was Director of Cell Biology at Celera where he oversaw research efforts to develop novel antibody-based therapeutics. Dr Moore received a PhD in molecular genetics from the University of Glasgow. He has an extensive research record co-authoring over 75 peer-reviewed manuscripts and is a named co-inventor on over 50 issued US patents.