ZW-191: A Folate Receptor Alpha-Targeting Antibody-Drug Conjugate for Oncological Applications

1. Executive Summary

ZW-191 is an investigational antibody-drug conjugate (ADC) engineered by Zymeworks Inc., targeting Folate Receptor alpha (FRα), a validated cell-surface antigen overexpressed in various solid tumors with high unmet medical need. The molecular architecture of ZW-191 comprises a novel humanized IgG1 antibody, a proprietary potent topoisomerase I inhibitor (TOPO1i) payload designated ZD06519, and a protease-cleavable linker system (maleimidocaproyl anchor with a GGFG-aminomethyl sequence), achieving a drug-to-antibody ratio (DAR) of 8.[1] This design reflects a strategic approach to optimize therapeutic efficacy, particularly in tumor microenvironments characterized by heterogeneous antigen expression, leveraging superior antibody internalization and a potent bystander-active payload.

Preclinical evaluations have demonstrated ZW-191's potent and selective anti-tumor activity. In vitro, the ADC exhibited sub-nanomolar binding affinity to FRα, superior cellular internalization, and efficient payload delivery, leading to cytotoxicity in FRα-expressing cancer cell lines and 3D tumor spheroids.[1] A significant bystander effect, mediated by the cell-permeable ZD06519 payload, was observed, enabling the killing of adjacent FRα-negative tumor cells.[1] In vivo, ZW-191 induced substantial tumor regressions in patient-derived xenograft (PDX) models of ovarian cancer, non-small cell lung cancer (NSCLC), endometrial cancer, and triple-negative breast cancer (TNBC), critically, across a spectrum of FRα expression levels (high, mid, and low).[1] Comparative studies indicated superior or comparable activity to mirvetuximab soravtansine, especially in models with lower FRα expression.[2]

Non-human primate (NHP) toxicology studies revealed an encouraging safety profile, with ZW-191 being well-tolerated up to 60 mg/kg (Q3Wx3), established as the highest non-severely toxic dose (HNSTD).[2] Observed effects, primarily gastrointestinal and transient hematologic/biochemical changes, were generally non-adverse and reversible, and notably, no ophthalmic toxicities were reported.[2] The pharmacokinetic profile in NHPs was deemed favorable for clinical development.[1]

Clinically, ZW-191 is advancing under an Investigational New Drug (IND) application cleared by the U.S. Food and Drug Administration (FDA) in July 2024.[5] A global, multi-center, open-label Phase 1 clinical trial (NCT06555744; ZWI-ZW191-101) was initiated, with the first patient dosed in November 2024.[7] This two-part study aims to evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of ZW-191 in approximately 145 adult patients with advanced FRα-expressing solid tumors, including ovarian, endometrial, and NSCLC.[10] The development of ZW-191, particularly its potential efficacy in tumors with low or heterogeneous FRα expression, positions it to address significant unmet medical needs and could validate Zymeworks' broader ADC platform technologies.

2. Introduction to ZW-191: A Novel Folate Receptor Alpha (FRα)-Targeting Antibody-Drug Conjugate

Antibody-drug conjugates (ADCs) have emerged as a transformative class of therapeutics in oncology, designed to selectively deliver potent cytotoxic agents to cancer cells while minimizing systemic exposure and associated toxicities. This targeted approach is achieved by linking a monoclonal antibody, specific for a tumor-associated antigen, to a cytotoxic payload via a stable linker. The evolving landscape of ADC technology focuses on optimizing each component—antibody, linker, and payload—to enhance the therapeutic index.

Within this context, Zymeworks Inc. is developing ZW-191, a novel investigational ADC targeting Folate Receptor alpha (FRα).[1] FRα is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein with limited expression in normal adult tissues but is frequently overexpressed in a variety of epithelial malignancies. These include ovarian cancer, endometrial cancer, non-small cell lung cancer (NSCLC), and triple-negative breast cancer (TNBC), among others, making it a clinically validated target for ADC development.[1] The therapeutic rationale for targeting FRα is underscored by the clinical validation provided by mirvetuximab soravtansine, an FRα-targeting ADC approved for certain ovarian cancers.[2]

Despite the clinical validation of FRα as an ADC target, a significant unmet need persists, particularly for patients whose tumors exhibit low or heterogeneous FRα expression. For instance, it is estimated that approximately two-thirds of ovarian cancer patients may not be eligible for treatment with mirvetuximab soravtansine due to insufficient FRα expression levels based on current diagnostic criteria.[2] ZW-191 has been engineered with distinct molecular features, including a novel antibody with enhanced internalization properties and a potent bystander-active payload, aimed at addressing these limitations. Preclinical data suggest that ZW-191 may offer improved efficacy, especially in tumors with lower FRα expression, potentially expanding the patient population that could benefit from FRα-targeted ADC therapy.[2] The development of ZW-191 thus represents an effort to build upon existing knowledge in FRα targeting, aiming to deliver a more effective therapeutic option across a broader range of FRα-expressing cancers.

3. Molecular Profile and Mechanism of Action of ZW-191

ZW-191 is a complex macromolecular therapeutic, meticulously designed with distinct components that synergistically contribute to its targeted anti-tumor activity. Its structure and mechanism reflect advancements in ADC engineering aimed at maximizing efficacy and improving the therapeutic window.

Table 1: Summary of ZW-191 Molecular Characteristics

Component	Description/Properties	Source Snippet(s)
Antibody	Novel, fully humanized IgG1; targets human Folate Receptor alpha (FRα); engineered for superior internalization, payload delivery, and tumor spheroid penetration; sub-nanomolar binding affinity.	1
Payload	ZD06519: a novel, proprietary, rationally designed, moderate potency, bystander-active camptothecin-based topoisomerase I inhibitor (TOPO1i).	1
Linker	Maleimidocaproyl (MC) anchor and a glycyl glycyl phenylalanyl glycyl (GGFG)-aminomethyl (AM) protease-cleavable sequence; conjugates payload to antibody via endogenous interchain cysteines.	1
DAR	Drug-to-Antibody Ratio of 8; selected to balance efficacy and tolerability.	2

Antibody Component:

The targeting moiety of ZW-191 is a novel, fully humanized immunoglobulin G1 (IgG1) monoclonal antibody.2 This antibody was specifically selected for its high affinity and specificity for human FRα, exhibiting sub-nanomolar binding capabilities.2 A critical feature of this antibody is its enhanced internalization characteristics. Compared to other FRα-targeted antibodies used in ADC development, the ZW-191 antibody has demonstrated superior efficiency in cellular internalization following FRα binding, leading to more effective payload delivery into the tumor cell and enhanced penetration into tumor spheroids, which mimic aspects of the solid tumor microenvironment.1 This improved intracellular trafficking is a key attribute, as efficient delivery of the cytotoxic payload to its site of action is paramount for ADC efficacy.

Payload: ZD06519

The cytotoxic component of ZW-191 is ZD06519, a novel, proprietary topoisomerase I inhibitor (TOPO1i) based on a camptothecin scaffold.1 ZD06519 was rationally designed for moderate potency and, significantly, possesses bystander activity.2 Topoisomerase I is an essential enzyme involved in DNA replication and transcription; its inhibition leads to DNA strand breaks and ultimately, apoptotic cell death. The bystander effect means that once ZD06519 is released within a target FRα-positive cell, it can diffuse through cell membranes to kill nearby FRα-negative tumor cells, a property particularly advantageous in tumors with heterogeneous antigen expression.1 Zymeworks has highlighted ZD06519 as a key component of its ADC platform, with plans to utilize this payload in other ADC candidates (ZW220 and ZW251).5

Linker Technology:

ZW-191 employs a protease-cleavable linker system to attach the ZD06519 payload to the antibody. This linker consists of a maleimidocaproyl (MC) anchor, which facilitates conjugation to cysteine residues on the antibody, and a peptide sequence, glycyl glycyl phenylalanyl glycyl (GGFG)-aminomethyl (AM).1 The GGFG motif is designed to be selectively cleaved by lysosomal proteases, such as cathepsin B, which are abundant within the intracellular environment of tumor cells after ADC internalization. This ensures that the payload is preferentially released within the target cell, minimizing premature release in systemic circulation and thereby reducing off-target toxicity. The conjugation occurs via endogenous interchain cysteines of the antibody.2

Drug-to-Antibody Ratio (DAR):

ZW-191 is engineered with a drug-to-antibody ratio (DAR) of 8.2 This relatively high DAR means that, on average, eight molecules of the ZD06519 payload are attached to each antibody molecule. The selection of DAR 8 was a deliberate choice aimed at maximizing the cytotoxic payload delivered per antibody binding event, while seeking an optimal balance between anti-tumor efficacy and systemic tolerability.5

Detailed Mechanism of Action (MOA):

The anti-tumor activity of ZW-191 is a multi-step process:

1. Target Binding: ZW-191 circulates in the bloodstream and selectively binds to FRα expressed on the surface of tumor cells.[3]
2. Internalization: Upon binding, the ZW-191/FRα complex is internalized into the cell via receptor-mediated endocytosis.[1] The superior internalization properties of the ZW-191 antibody are critical at this stage.
3. Lysosomal Trafficking and Payload Release: The internalized ADC is trafficked to lysosomes, where the acidic environment and lysosomal proteases cleave the GGFG-AM linker, releasing the active ZD06519 payload into the cytoplasm.[3]
4. Cytotoxic Action: Free ZD06519, as a TOPO1i, intercalates into DNA and inhibits topoisomerase I activity. This leads to the accumulation of single-strand DNA breaks during DNA replication, ultimately triggering cell cycle arrest and apoptosis in the FRα-expressing tumor cell.[3]
5. Bystander Killing: A key feature of ZW-191 is the bystander effect of its ZD06519 payload. Being cell-permeable, the released ZD06519 can diffuse out of the targeted FRα-positive cell and penetrate adjacent tumor cells, including those that may not express FRα or express it at low levels. This bystander-mediated killing significantly enhances the ADC's anti-tumor activity, particularly in heterogeneous tumors where FRα expression can vary widely.[1]

The combination of a highly internalizing antibody, a potent TOPO1i payload with bystander activity, a stable yet cleavable linker, and a high DAR positions ZW-191 as an ADC engineered to overcome several common challenges in ADC therapy, such as poor tumor penetration and efficacy against tumors with heterogeneous or low antigen expression. This molecular design underpins its potential for a broad therapeutic window and activity across multiple cancer types.

4. Preclinical Pharmacology and Efficacy

The preclinical development of ZW-191 involved extensive in vitro and in vivo studies to characterize its pharmacological properties and anti-tumor efficacy. These studies have provided a strong rationale for its advancement into clinical trials.

In Vitro Studies:

• Binding Affinity and Internalization: The antibody component of ZW-191 was confirmed to bind with high affinity (sub-nanomolar) to FRα expressed on cancer cells.[2] Critically, this antibody demonstrated superior cellular internalization and subsequent payload delivery when compared to other FRα-targeting antibodies utilized in ADC development.[1] Quantitative analysis of internalized payload in IGROV-1 cells (an ovarian cancer cell line) after 24 hours of treatment further substantiated this enhanced delivery capability.[2]
• Cytotoxicity and Tissue Penetration: ZW-191 exhibited potent cytotoxic activity against various FRα-expressing cancer cell lines grown as 3D spheroids, including models of ovarian, lung, and endometrial cancer.[1] The pIC50​ values derived from these assays indicated robust cell-killing ability. The novel antibody component was also shown to facilitate superior penetration into these tumor spheroids, a property essential for efficacy in solid tumors where drug distribution can be challenging.[1]
• Bystander Activity Assessment: The bystander killing capacity of ZW-191, mediated by its ZD06519 payload, was effectively demonstrated using co-culture systems. In experiments where FRα-positive cells (e.g., IGROV-1) were co-cultured with FRα-negative cells (e.g., EBC-1, a lung cancer cell line), ZW-191 treatment led to a decrease in the viability of the FRα-negative cells, an effect not observed with non-bystander ADCs.[1] This bystander effect is considered crucial for achieving therapeutic responses in tumors with heterogeneous FRα expression, where not all cells within the tumor mass express the target antigen at high levels.[2]

In Vivo Anti-Tumor Activity (Patient-Derived Xenograft - PDX models):

ZW-191's anti-tumor activity was evaluated in a diverse panel of PDX models, which are generally considered more representative of human tumor biology than cell line-derived xenografts. Tumor regression was defined as a tumor volume change of less than 0% from baseline.2

• General Efficacy: Across various PDX models representing ovarian cancer, NSCLC, endometrial cancer, and TNBC, ZW-191 demonstrated compelling and robust anti-tumor activity.[1]
• Activity Across FRα Expression Levels: A key finding from the in vivo studies was the significant activity of ZW-191 across a wide range of FRα expression levels, including models classified as FRα-high, FRα-medium, and FRα-low.[1] This broad activity spectrum is a potential differentiating feature compared to other FRα-targeted therapies that may require high FRα expression for optimal efficacy.
• Comparative Efficacy (vs. Mirvetuximab Soravtansine): Head-to-head comparisons with mirvetuximab soravtansine, an approved FRα-targeting ADC, were conducted in several PDX models.
• Ovarian Cancer PDX Models: ZW-191 consistently demonstrated superior anti-tumor activity compared to mirvetuximab soravtansine in ovarian cancer PDX models with relatively low FRα expression (e.g., OVXF_1320_T with an H-score of 30, where ZW-191 induced tumor regression in 3/3 mice versus 0/3 for mirvetuximab soravtansine at a 6 mg/kg single dose).[2] In models with high FRα expression, ZW-191 showed activity that was superior or comparable to that of mirvetuximab soravtansine.[2]
• NSCLC, Endometrial Cancer, and TNBC PDX Models: Similar trends were observed in PDX models of other FRα-expressing cancers. ZW-191 exhibited superior or comparable anti-tumor activity to mirvetuximab soravtansine across these indications, often demonstrating efficacy in models with lower FRα H-scores where mirvetuximab soravtansine showed limited activity.[2] For example, in the LANOXF_A002_A NSCLC model (H-score 80), ZW-191 achieved tumor regression, whereas mirvetuximab soravtansine did not.[2]

Table 2: Illustrative Preclinical Efficacy Data of ZW-191 in Selected PDX Models

PDX Model	Cancer Type	FRα Expression (H-Score)	ZW-191 Dose (mg/kg, single)	ZW-191 Incidence of Tumor Regression	Mirvetuximab Soravtansine Dose (mg/kg, single)	Mirvetuximab Soravtansine Incidence of Tumor Regression	Source Snippet(s)
OVXF_630_T	Ovarian Cancer	240	6	3/3	6	3/3	2
OVXF_1320_T	Ovarian Cancer	30	6	3/3	6	0/3	2
LGXF_2121_T	NSCLC	210	6	Not explicitly stated, strong TGI	6	Not explicitly stated, less TGI	2
LANOXF_A002_A	NSCLC	80	6	Tumor Regression (visual)	6	No Regression (visual)	2
ENDOXF_A001_B	Endometrial Cancer	165	6	Tumor Regression (visual)	6	Less Regression (visual)	2
BRXF_2553_T	TNBC	80	6	Tumor Regression (visual)	6	No Regression (visual)	2

Note: "Tumor Regression" typically defined as <0% change from baseline tumor volume. TGI = Tumor Growth Inhibition. H-score determined by pathologist from research level IHC assay. Data often presented visually in source figures.

The consistent outperformance or equivalence of ZW-191 against mirvetuximab soravtansine, particularly in models with low FRα expression, supports the hypothesis that ZW-191's unique design attributes—specifically its highly internalizing antibody and potent bystander payload—may translate to clinical benefit in a broader patient population than currently addressable by existing FRα-targeted ADCs. The robust bystander effect is a critical component of this potential, offering a mechanism to overcome intra-tumoral heterogeneity, a common cause of therapeutic resistance.

5. Non-Human Primate (NHP) Pharmacokinetics and Toxicology

To assess the safety and pharmacokinetic profile of ZW-191 prior to human clinical trials, comprehensive studies were conducted in non-human primates (NHPs), specifically cynomolgus monkeys. These studies are crucial for identifying potential toxicities, establishing a safe starting dose for human trials, and understanding the drug's behavior in a biological system more complex than rodent models.

Pharmacokinetic (PK) Profile:

ZW-191 demonstrated a favorable pharmacokinetic profile in NHPs.1 While specific PK parameters such as half-life, clearance, and area under the curve (AUC) were not detailed in the available abstracts, the overall assessment indicated that the PK characteristics support the planned clinical dosing schedules, typically involving intermittent administration (e.g., every three weeks, Q3W).2

Safety and Tolerability Studies:

A Good Laboratory Practice (GLP) repeat-dose toxicology study was performed in NHPs, with ZW-191 administered every three weeks for three cycles (Q3Wx3).2

• Overall Tolerability: ZW-191 was reported to be well-tolerated, with an encouraging overall tolerability profile.[1]
• Highest Non-Severely Toxic Dose (HNSTD): The HNSTD for ZW-191 in this NHP study was established at 60 mg/kg.[2] This dose level was reported to be above the exposure levels projected to be efficacious based on preclinical tumor models [13], suggesting a potentially favorable therapeutic index.
• Mortality and Body Weight: No mortality or significant adverse effects on body weight were observed across the tested dose levels.[2]
• Ophthalmic Effects: Importantly, no ophthalmic toxicities were noted during the NHP studies.[2] This is a significant finding, as ocular adverse events can be a dose-limiting toxicity for some classes of ADCs, particularly those with microtubule-inhibiting payloads.
• Observed Effects (Dose-Dependent and Reversible): The study identified dose-dependent findings, all ofwhich were characterized as non-adverse and reversible upon cessation of treatment.2 Table 3: Summary of NHP Toxicology Findings for ZW-191 (Q3Wx3 Study)

Dose Level (mg/kg)	Key Clinical Observations	Histopathological Findings	Clinical Chemistry Changes	Overall Assessment (Adverse/Non-Adverse, Reversibility)	Source Snippet(s)
10	No adverse effects reported	No adverse effects reported	Slight, transient ↑ AST, ALT (n=1)	Non-adverse, Reversible	2
30	Emesis/vomitus	↓ Thymic lymphocytes, ↓ Pancreatic acinar cell secretion	↑ AST, ALT	Non-adverse, Reversible	2
60	Liquid/discolored feces, Emesis/vomitus, ↓ Activity level (n=1)	↓ Thymic lymphocytes, ↓ Pancreatic acinar cell secretion	↑ AST, ALT, ↑ Creatine Kinase (CK)	Non-adverse, Reversible	2

*AST = Aspartate Aminotransferase; ALT = Alanine Aminotransferase; CK = Creatine Kinase.*

The NHP toxicology data, particularly the establishment of an HNSTD at 60 mg/kg and the reversible nature of the observed effects (primarily gastrointestinal disturbances and transient changes in lymphocyte counts, pancreatic enzyme indicators, and liver enzymes), provided a solid basis for proceeding to Phase 1 clinical trials. The absence of irreversible or life-threatening toxicities at clinically relevant exposures was encouraging. However, the consistent findings of decreased thymic lymphocytes and pancreatic acinar cell secretion at the higher doses (30 and 60 mg/kg), even if deemed non-adverse and reversible in NHPs, highlight these as areas for careful monitoring in human subjects during early clinical development. The clinical significance of these observations, especially under conditions of repeated dosing in patients, will need to be thoroughly evaluated.

6. Clinical Development Program: The ZWI-ZW191-101 (NCT06555744) Study

Following the promising preclinical data and favorable NHP toxicology profile, ZW-191 has transitioned into clinical development.

Regulatory Milestone:

The Investigational New Drug (IND) application for ZW-191 was cleared by the U.S. Food and Drug Administration (FDA) in July 2024.5 This clearance paved the way for the initiation of the first-in-human clinical trial. Zymeworks also indicated plans to file for regulatory authorization to commence clinical studies in non-US jurisdictions in the second half of 2024.5

Study Identification:

The ongoing Phase 1 clinical trial is identified as:

• ClinicalTrials.gov ID: NCT06555744 [7]
• Primary ID (Sponsor ID): ZWI-ZW191-101 [10]
• Secondary IDs include: NCI-2025-02051 and the EudraCT number 2024-512299-37-00.[10]

Study Design:

The ZWI-ZW191-101 study is a Phase 1, first-in-human, open-label, multi-center, global trial.7 It is structured in two parts:

• Part 1 (Dose Escalation): This part will evaluate the safety and tolerability of increasing doses of ZW-191 to determine the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D).
• Part 2 (Dose Expansion): This part will further assess the safety, tolerability, and preliminary anti-tumor activity of ZW-191 at the determined RP2D in specific patient cohorts.

Table 4: Overview of NCT06555744 (ZWI-ZW191-101) Clinical Trial Design

Feature	Details	Source Snippet(s)
Study Title	A Study of ZW191 in Participants With Solid Tumors	10
ClinicalTrials.gov ID	NCT06555744	7
Phase	Phase 1	3
Study Design	Two-part (Dose Escalation, Dose Expansion), Open-label, Multi-center, Global, Single-arm (in dose escalation)	10
Primary Objectives	Part 1: Evaluate safety and tolerability of ZW-191, determine MTD/RP2D. Part 2: Further evaluate safety and explore potential anti-tumor activity.	7
Key Secondary Objectives	Assess pharmacokinetics (PK) and confirmed objective response rate (ORR) per RECIST v1.1.	7
Target Indications	Advanced FRα-expressing solid tumors, specifically including ovarian cancer, endometrial cancer, and non-small cell lung cancer (NSCLC).	3
Key Inclusion Criteria	Pathologically/cytologically confirmed advanced (unresectable), recurrent/metastatic disease; measurable disease per RECIST v1.1; ECOG PS 0 or 1; LVEF ≥ 50%; adequate organ function.	10
Key Exclusion Criteria	Progressing additional malignancy requiring active treatment; prior Topoisomerase I inhibitor (TOPO1i) ADC treatment; uncontrolled renal/pancreatic/liver disease; severe active infections.	10
Estimated Enrollment	Approximately 145 adult patients.	7
Current Status	Active, Recruiting.	7
Key Timelines	IND Cleared: July 2024. First Patient Dosed: November 2024. Planned TiP Poster: ESMO Gynaecological Cancers Congress, June 2025.	5

Target Population:

The study aims to enroll approximately 145 adult patients with pathologically or cytologically confirmed advanced FRα-expressing solid tumors that are locally advanced (unresectable), recurrent, or metastatic.7 Specific tumor types of interest include ovarian cancer, endometrial cancer, and NSCLC.3

Key inclusion criteria mandate measurable disease according to RECIST v1.1, an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1, adequate cardiac function (defined as Left Ventricular Ejection Fraction (LVEF) ≥ 50%), and other adequate organ function.10

Notable exclusion criteria include any known additional malignancy that is progressing or requires active treatment, or that may interfere with study endpoints. Critically, patients who have received prior treatment with a Topoisomerase I inhibitor (TOPO1i) ADC are excluded, regardless of the washout period.10 Other exclusions comprise acute or chronic uncontrolled renal disease, pancreatitis, or liver disease, and severe chronic or active infections requiring systemic therapy.10 The exclusion of patients with prior TOPO1i ADC exposure is a significant aspect of the trial design. This ensures that the initial assessment of ZW-191's safety and efficacy is not confounded by potential pre-existing resistance mechanisms or cumulative toxicities from similar payloads. While this approach provides a cleaner dataset for initial evaluation, it means that the trial will not immediately address the activity of ZW-191 in the TOPO1i-ADC refractory setting, which is an increasingly relevant clinical scenario as TOPO1i ADCs become more widely used.

Current Status and Timelines:

The ZWI-ZW191-101 trial is currently active and recruiting participants.7 The first patient was dosed in November 2024.7 The relatively rapid transition from IND clearance in July 2024 to the first patient being dosed suggests efficient operational planning and a high priority for the ZW-191 program within Zymeworks.

Trial Locations:

The study is being conducted at investigator sites across North America (including Connecticut and Ohio in the US), Europe, and the Asia-Pacific region.7 The NCI website lists three active locations.20 The global nature of the trial is intended to facilitate timely patient accrual and generate data applicable to diverse regulatory environments.

Planned Communications:

Zymeworks plans to present a Trial-in-Progress (TiP) poster for the ZWI-ZW191-101 study at the European Society of Medical Oncology (ESMO) Gynaecological Cancers Congress, scheduled for June 19-21, 2025.14 This will likely be one of the first public disclosures of the trial design and early progress to the oncology community.

7. Therapeutic Rationale and Potential Clinical Utility

The development of ZW-191 is grounded in a strong therapeutic rationale centered on the characteristics of its target, FRα, and the specific design features of the ADC intended to address unmet clinical needs.

Folate Receptor Alpha (FRα) as a Therapeutic Target:

• Clinical Validation: FRα is a clinically validated target for ADC therapy. The approval of mirvetuximab soravtansine (Elahere™) for FRα-positive, platinum-resistant ovarian cancer has established FRα as an actionable antigen in oncology.[1]
• Expression Profile: FRα exhibits a favorable expression profile for targeted therapy. It is prevalently expressed at moderate to high levels in a significant proportion of several difficult-to-treat cancers, including approximately 75% of ovarian carcinomas, around 70% of NSCLCs (particularly adenocarcinomas), and about 50% of endometrial cancers, as well as in TNBC.[1] Conversely, its expression in normal adult tissues is limited, primarily restricted to the apical surfaces of some polarized epithelia, which are often not readily accessible to intravenously administered antibodies. This differential expression provides a therapeutic window for FRα-targeted ADCs.

Addressing Unmet Needs:

ZW-191 aims to address several unmet needs in the treatment of FRα-expressing cancers:

• Activity in Low FRα Expressors: A major limitation of some existing FRα-targeted therapies is their reliance on high levels of FRα expression for optimal efficacy. It is estimated that a substantial fraction of patients, for example, up to two-thirds of those with ovarian cancer, may have tumors with FRα expression levels considered too low for eligibility or optimal response to therapies like mirvetuximab soravtansine.[2] ZW-191's preclinical data, demonstrating robust anti-tumor activity in PDX models with FRα-high, -medium, and critically, -low expression, suggests it has the potential to be effective in this underserved patient population.[1] This ability to target a broader range of FRα expression could significantly expand the number of patients who could benefit from FRα-directed ADC therapy, potentially making FRα a more universally applicable target.
• Overcoming Tumor Heterogeneity with Bystander Effect: Solid tumors are often characterized by intra-tumoral heterogeneity, where the expression of a target antigen like FRα can vary significantly between different cancer cells within the same tumor. This heterogeneity can lead to incomplete tumor responses and the emergence of resistance. The ZD06519 payload of ZW-191 is designed to be bystander active, meaning that once released from a targeted FRα-positive cell, it can diffuse and kill nearby FRα-negative or low-expressing cancer cells.[1] This mechanism is crucial for achieving more comprehensive tumor cell killing in heterogeneous environments and may lead to more durable clinical responses.
• Potential for Improved Efficacy and/or Tolerability: ZW-191 incorporates a novel antibody selected for superior internalization and payload delivery, and a novel TOPO1i payload. This combination is intended to improve upon the efficacy and/or tolerability profile of existing FRα-targeted therapies.[2] If clinical data validates this, ZW-191 could offer a better therapeutic option for patients with FRα-positive cancers.

Potential Advantages of ZW-191:

Based on its design and preclinical data, ZW-191 may offer several advantages:

• Novel Antibody Component: The proprietary humanized IgG1 antibody in ZW-191 is reported to exhibit superior internalization kinetics, more efficient payload delivery, and better tumor spheroid penetration compared to other FRα-targeted antibodies.[1] These characteristics are fundamental to maximizing the amount of cytotoxic payload that reaches the intracellular target.
• Novel ZD06519 Payload: ZD06519 is a rationally designed TOPO1i payload with moderate potency and significant bystander activity, engineered to balance anti-tumor efficacy with systemic tolerability.[2] The TOPO1i class of payloads has demonstrated significant clinical success in other ADCs.
• Broader Patient Population: The most significant potential advantage lies in ZW-191's ability to treat patients with a wider spectrum of FRα expression levels, including those with low expression who are currently ineligible for or unlikely to respond to existing FRα-targeted ADCs. Furthermore, its activity in preclinical models of NSCLC, endometrial cancer, and TNBC suggests potential utility beyond ovarian cancer.[2]

The successful clinical development of ZW-191, particularly if it demonstrates efficacy in tumors with low or heterogeneous FRα expression, could not only provide a new treatment option for patients but also stimulate further research into optimizing ADC components for targets that present similar expression challenges. This could influence broader strategies in ADC development for various solid tumors.

8. Regulatory Status and Future Perspectives

The regulatory journey and future development path for ZW-191 are critical determinants of its potential translation into a clinical therapy.

Current Regulatory Milestones:

• U.S. Food and Drug Administration (FDA): A significant milestone was achieved in July 2024 with the FDA's clearance of the Investigational New Drug (IND) application for ZW-191.[5] This regulatory green light permitted the initiation of the Phase 1 clinical trial (NCT06555744) in the United States.
• Ex-U.S. Regulatory Filings: Zymeworks has indicated its intention to file applications seeking regulatory authorization to initiate clinical studies for ZW-191 in non-US jurisdictions during the second half of 2024.[5] This suggests a strategy for global clinical development.

Special Designations:

Based on the provided information, ZW-191 has not yet received any specific FDA or European Medicines Agency (EMA) special designations such as Orphan Drug Designation, Fast Track Designation, or Breakthrough Therapy Designation.14 While Zymeworks has experience securing such designations for other product candidates in its pipeline (e.g., zanidatamab received Fast Track and Breakthrough Therapy designations 29), these have not been reported for ZW-191 to date. The absence of these designations at this early stage is not unusual, as they are often granted based on emerging clinical data that demonstrates a potential to address serious conditions and unmet medical needs, or offer substantial improvement over available therapies. As clinical data from the Phase 1 trial become available, Zymeworks may pursue such designations if the results are compelling.

Future Perspectives:

The future development of ZW-191 hinges on the outcomes of its ongoing clinical program:

• Progression of Phase 1 Trial (NCT06555744): The immediate focus is on the successful completion of the dose escalation (Part 1) to establish the MTD and/or RP2D, followed by the dose expansion (Part 2) to gather more extensive safety and preliminary efficacy data in targeted patient populations.
• Data Readouts: Initial data on safety, pharmacokinetics, and any early signals of anti-tumor activity from the Phase 1 trial will be critical. An early glimpse into the trial's progress is anticipated with the planned Trial-in-Progress poster presentation at the ESMO Gynaecological Cancers Congress in June 2025.[14] Subsequent, more mature data readouts will be pivotal for decision-making.
• Further Clinical Development: Contingent upon positive Phase 1 results, ZW-191 would likely advance to Phase 2 and potentially Phase 3 trials. These trials would further evaluate its efficacy and safety in specific FRα-expressing cancer types and patient populations, possibly including those with low FRα expression, which is a key area of interest based on preclinical findings.
• Impact on Zymeworks' ADC Pipeline: ZW-191 is the first of three ADC candidates from Zymeworks that incorporate the proprietary ZD06519 TOPO1i payload to enter clinical trials. The other candidates are ZW220 (targeting NaPi2b) and ZW251 (targeting GPC3), with IND filings anticipated for 2025.[5] The clinical performance of ZW-191, particularly its safety profile related to the ZD06519 payload and the linker technology, will significantly inform and potentially validate the broader application of this payload platform in Zymeworks' ADC pipeline.

ZW-191's development timeline, with IND clearance in mid-2024 and the first patient dosed by late 2024, positions it within a competitive and rapidly evolving field of FRα-targeting ADCs and TOPO1i-based ADCs. Its ability to quickly generate compelling Phase 1 data demonstrating a favorable safety profile and efficacy, especially in tumors with low or heterogeneous FRα expression, will be crucial for its differentiation and continued advancement.

9. Expert Synthesis and Outlook

ZW-191 emerges from preclinical studies as a rationally designed, next-generation antibody-drug conjugate with several features that suggest potential advantages in the treatment of Folate Receptor alpha (FRα)-expressing solid tumors. Its core design elements—a novel humanized IgG1 antibody with superior internalization properties, a potent and bystander-active topoisomerase I inhibitor payload (ZD06519), a stable yet protease-cleavable linker, and a high drug-to-antibody ratio of 8—collectively aim to maximize targeted payload delivery and anti-tumor efficacy, particularly in challenging tumor contexts.[1]

The preclinical data package for ZW-191 is compelling. The consistent demonstration of potent in vitro cytotoxicity, effective bystander killing, and significant in vivo anti-tumor activity in diverse patient-derived xenograft models—importantly, including those with low and heterogeneous FRα expression—highlights its potential to address a broader patient population than some existing FRα-targeted therapies.[1] The head-to-head preclinical superiority or comparability to mirvetuximab soravtansine, especially in low FRα settings, further underscores this potential.[2] The non-human primate toxicology studies indicate a manageable safety profile, with an HNSTD of 60 mg/kg and reversible, non-adverse findings at higher doses, and notably, an absence of ophthalmic toxicity, which can be a concern with other ADC classes.[2]

The program has smoothly transitioned into early-stage clinical development with the FDA clearance of its IND in July 2024 and the initiation of the global Phase 1 trial (NCT06555744; ZWI-ZW191-101) in November 2024.[5] This trial will provide the first human data on the safety, tolerability, pharmacokinetics, and preliminary efficacy of ZW-191 in patients with advanced FRα-expressing cancers, including ovarian, endometrial, and non-small cell lung cancers.

Several factors will be critical to ZW-191's future success. Firstly, the translation of the NHP safety profile to humans will be closely watched. While the observed toxicities in NHPs (such as decreased thymic lymphocytes and pancreatic acinar cell secretion) were deemed non-adverse and reversible, their clinical manifestation and manageability in cancer patients, who may have different underlying physiological states and co-morbidities, will need careful evaluation.[2] Secondly, managing potential TOPO1i class-related toxicities (e.g., myelosuppression, gastrointestinal effects) will be important, although the specific profile of ZD06519 may differ from other TOPO1i payloads. Thirdly, the competitive landscape for FRα-targeted therapies and for ADCs employing TOPO1i payloads is dynamic and expanding. ZW-191's differentiation, particularly its efficacy in low FRα expressors and its bystander mechanism, will need to be clearly demonstrated in clinical settings to establish its unique value proposition.

The upcoming Trial-in-Progress poster at the ESMO Gynaecological Cancers Congress in June 2025 is anticipated to provide early insights into the clinical trial's conduct.[14] Subsequent data readouts from the Phase 1 study will be pivotal in validating the therapeutic potential and safety of ZW-191. If successful, ZW-191 could not only offer a significant new treatment option for patients with a range of FRα-expressing cancers, potentially including those currently underserved by existing therapies, but also validate Zymeworks' ZD06519 payload technology for its broader ADC pipeline. The journey of ZW-191 from preclinical promise to potential clinical impact is at an early but critical stage, with the oncology community keenly awaiting the emergence of human data.

Works cited

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