JSKN-003: A Comprehensive Clinical and Scientific Dossier

Executive Summary

JSKN-003 is an investigational, next-generation antibody-drug conjugate (ADC) engineered to target the human epidermal growth factor receptor 2 (HER2). Developed by Alphamab Oncology, it represents a significant evolution in ADC technology, integrating multiple proprietary innovations to enhance efficacy and broaden the therapeutic window.[1] The core structure of JSKN-003 is built upon KN026, a biparatopic antibody that uniquely binds to two distinct epitopes on the HER2 receptor. This antibody is site-specifically conjugated to a potent topoisomerase I inhibitor payload using a proprietary glycan-specific platform, resulting in a highly stable and homogenous therapeutic agent with a powerful bystander effect.[1]

The clinical development program for JSKN-003 has yielded compelling data across multiple heavily pretreated solid tumor indications, most notably in platinum-resistant ovarian cancer (PROC) and HER2-positive breast cancer. In a pooled analysis of patients with PROC, JSKN-003 demonstrated a transformative objective response rate (ORR) of 64.4% and a median progression-free survival (PFS) of 7.1 months, far exceeding historical benchmarks for standard-of-care chemotherapy.[3] A landmark finding from these studies is the drug's profound activity in patients with HER2-negative (immunohistochemistry [IHC] 0) tumors, challenging the conventional biomarker-driven paradigm for HER2-targeted agents and suggesting a potential HER2-agnostic role in this setting.

In heavily pretreated, HER2-positive breast cancer, JSKN-003 has shown a robust ORR of 67.9% in patients naïve to trastuzumab deruxtecan (T-DXd).[4] Critically, it has also demonstrated clinical activity in patients whose disease has progressed after treatment with T-DXd, addressing a significant and growing unmet medical need.[4] The safety profile of JSKN-003 has been consistently manageable and well-tolerated across studies. Treatment-related adverse events (TRAEs) are predominantly low-grade gastrointestinal toxicities, with a notably low incidence of severe (Grade $\ge3$) hematological events and, most importantly, a low rate of interstitial lung disease (ILD)—a key safety concern for this class of ADCs.[3]

The promising clinical profile of JSKN-003 has been recognized by global regulatory agencies, with multiple Breakthrough Therapy Designations granted by China's National Medical Products Administration (NMPA) for PROC and colorectal cancer (CRC), and an Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for gastric cancer.[6] Supported by a strategic licensing agreement with CSPC Pharmaceutical Group for the Greater China market, JSKN-003 is being advanced through an aggressive global development plan, including multiple pivotal Phase III trials. Collectively, the evidence suggests that JSKN-003 is a highly innovative ADC with the potential to redefine treatment standards and expand the utility of HER2-targeted therapy to a much broader population of cancer patients.

JSKN-003: A Novel Biparatopic Anti-HER2 Antibody-Drug Conjugate

The unique therapeutic profile of JSKN-003 is a direct result of its sophisticated molecular architecture, which optimizes each of the three core components of an ADC: the antibody, the cytotoxic payload, and the linker-conjugation technology. This design represents a deliberate effort to overcome the limitations of earlier-generation ADCs by enhancing tumor-targeting specificity, maximizing payload potency, and ensuring systemic stability.

The Biparatopic Antibody Backbone: KN026

The foundation of JSKN-003 is KN026, a recombinant, humanized bispecific antibody that serves as the targeting vehicle.[2] Unlike conventional monospecific anti-HER2 antibodies such as trastuzumab or pertuzumab, which each bind to a single epitope, KN026 is engineered to simultaneously engage two distinct, non-overlapping epitopes on the extracellular domain (ECD) of the HER2 receptor. Specifically, it targets ECD II, the binding site for pertuzumab, and ECD IV, the binding site for trastuzumab.[2]

This dual-binding mechanism is hypothesized to confer several therapeutic advantages. By cross-linking HER2 receptors on the cell surface, KN026 is believed to induce more efficient receptor clustering and subsequent internalization compared to its monospecific counterparts. This enhanced internalization is a critical factor for an ADC, as it directly facilitates the delivery of the cytotoxic payload into the tumor cell. Furthermore, by blocking two key domains simultaneously, KN026 provides a more comprehensive blockade of downstream HER2 signaling pathways, which are crucial drivers of tumor cell proliferation and survival. This dual action provides an independent anti-tumor effect that complements the cytotoxicity of the attached payload.[4]

The Cytotoxic Payload: A Topoisomerase I Inhibitor

JSKN-003 is armed with a highly potent topoisomerase I inhibitor (TOPIi) payload.[1] Topoisomerase I is a critical nuclear enzyme responsible for relieving torsional strain in DNA during replication and transcription. By inhibiting this enzyme, the payload induces the accumulation of single-strand DNA breaks, which are converted into lethal double-strand breaks during the S-phase of the cell cycle, ultimately triggering apoptosis.[11]

This payload is part of Alphamab's proprietary "Alphatecan" platform and is described in some literature as a deruxtecan-like molecule (DXd).[1] The selection of a TOPIi payload is strategic, as this class has demonstrated exceptional potency and a strong bystander effect in other successful ADCs. The payload's ability to permeate cell membranes after its release within the target cell is a key feature of its mechanism of action.

Proprietary Conjugation Technology: Glycan-Specific Ligation

A defining feature of JSKN-003 is the advanced method used to attach the payload to the antibody. It employs Alphamab's proprietary "Glycan-specific Conjugation platform," a site-specific technology that leverages enzyme catalysis and click chemistry to attach the payload to the N-glycosylation sites of the KN026 antibody.[1] The payload is connected via a dibenzocyclooctyne tetrapeptide linker, which is designed to be stable in systemic circulation but efficiently cleaved within the lysosomal compartment of tumor cells.[2]

This approach yields a highly homogenous product with a consistent drug-to-antibody ratio (DAR) of approximately 4.[1] This uniformity is a major advantage over traditional conjugation methods, which often produce a heterogeneous mixture of ADC species with varying DARs. A consistent DAR ensures predictable pharmacokinetics, a more uniform biological activity, and a better-defined therapeutic index.

Resulting Molecular Advantages

The convergence of these three innovations—biparatopic targeting, a potent TOPIi payload, and site-specific conjugation—endows JSKN-003 with several key advantages. The glycan-specific conjugation and stable linker chemistry result in superior serum stability, minimizing the premature release of the toxic payload into the bloodstream. This property is crucial for reducing off-target toxicities and was clinically validated in human pharmacokinetic studies, which showed very low systemic exposure to the free payload.[5] By combining high on-target potency with improved systemic safety, JSKN-003 is designed to possess an expanded therapeutic window, allowing for the administration of clinically effective doses with a manageable toxicity profile.[1]

Pharmacological Profile and Mechanism of Action

The therapeutic effect of JSKN-003 is achieved through a multi-step process that begins with precise binding to tumor cells and culminates in widespread, localized cytotoxicity. This mechanism not only targets HER2-expressing cells but also extends its lethal effect to neighboring tumor cells, a property that underpins its activity in tumors with low or heterogeneous antigen expression.

High-Affinity, Dual-Epitope Binding to HER2

The process is initiated by the high-affinity binding of the JSKN-003 antibody component to the HER2 receptor on the surface of tumor cells. The binding affinity, with a dissociation constant ($K_D$) of $2.209 \times 10^{-10}$ M, is comparable to that of its parent antibody, KN026, ensuring efficient and stable engagement with the target.[2] The simultaneous binding to both ECD II and ECD IV of HER2 is a critical first step that enhances the avidity of the interaction and promotes receptor clustering on the cell surface.

Enhanced Internalization and Lysosomal Trafficking

Following binding, the JSKN-003-HER2 complex is rapidly internalized by the tumor cell through a process of target-mediated endocytosis.[1] Preclinical studies have shown that JSKN-003 undergoes more extensive and faster internalization compared to the benchmark ADC, trastuzumab deruxtecan (DS-8201), in HER2-positive cell lines.[2] This superior uptake efficiency is a key advantage, as it increases the amount of cytotoxic payload delivered into each target cell. Once inside the cell, the endocytic vesicle containing the ADC is trafficked through the endo-lysosomal pathway.

Intracellular Payload Release and Cytotoxicity

Within the acidic and enzyme-rich environment of the lysosome, the cleavable tetrapeptide linker is degraded, liberating the potent topoisomerase I inhibitor payload from the antibody.[1] The freed payload is then able to translocate from the lysosome into the cytoplasm and subsequently into the nucleus. Inside the nucleus, it binds to the topoisomerase I-DNA complex, preventing the re-ligation of single-strand DNA breaks. This leads to the accumulation of DNA damage, cell cycle arrest, and ultimately, the induction of apoptosis.[11]

The Potent Bystander Effect

A crucial element of JSKN-003's mechanism is the potent "bystander effect" attributed to its membrane-permeable payload.[1] After being released inside the target HER2-expressing cell, the payload can diffuse across the cell membrane and enter adjacent tumor cells, irrespective of their HER2 expression status.[1] This localized diffusion of a highly cytotoxic agent effectively turns the initial target cell into a "drug depot," enabling the killing of surrounding antigen-negative or low-expressing cancer cells.

This bystander killing mechanism is the pharmacological basis for the remarkable clinical efficacy observed in tumors with low or heterogeneous HER2 expression, including those classified as HER2-negative (IHC 0) by standard pathology.[3] The combination of enhanced internalization into cells with even low levels of HER2 and the subsequent diffusion of the payload to nearby cells creates a powerful synergistic effect. This two-step process allows JSKN-003 to overcome tumor heterogeneity, a common mechanism of resistance to targeted therapies, and provides a strong mechanistic rationale for its broad activity across different HER2 expression levels.

Preclinical Evidence: Efficacy and Safety Foundation

The clinical development of JSKN-003 was supported by a robust preclinical data package that established its potent anti-tumor activity, favorable pharmacokinetic profile, and acceptable safety margin. These foundational studies not only provided the rationale for first-in-human trials but were also highly predictive of the drug's eventual clinical performance.

In Vitro Anti-Tumor Activity

In laboratory studies, JSKN-003 demonstrated concentration-dependent binding to various HER2-positive cancer cell lines, including NCI-N87 (gastric cancer) and BxPC-3 (pancreatic cancer), confirming its ability to engage its target.[2] The drug exhibited direct and potent growth-inhibitory effects in HER2-positive tumor models such as NCI-N87 and BT474 (breast cancer).[2] A particularly important finding was that JSKN-003 retained its cytotoxic activity against trastuzumab-resistant cells. This suggested that its mechanism of action—primarily driven by efficient payload delivery rather than just HER2 signal blockade—could overcome a prevalent form of clinical resistance to standard HER2-targeted therapies.[14]

In Vivo Efficacy in Animal Models

The anti-tumor activity of JSKN-003 was further validated in vivo using both cell-derived xenograft (CDX) and more clinically relevant patient-derived xenograft (PDX) models. These studies were instrumental in demonstrating that JSKN-003 possessed a good safety profile and potent efficacy in models with both high and low levels of HER2 expression.[1] This early evidence of activity in HER2-low settings was a critical piece of data that informed the decision to pursue clinical trials in broader patient populations beyond just HER2-positive tumors. The drug induced significant tumor regression in multiple HER2-expressing tumor models, providing strong proof-of-concept for its therapeutic potential.[14]

Non-Human Primate (NHP) Pharmacokinetics and Toxicology

To assess its safety and pharmacokinetic profile before human administration, JSKN-003 was studied in cynomolgus monkeys. Pharmacokinetic analyses revealed that the ADC, the total antibody, and the released payload (DXd) exhibited general linear dynamic characteristics across a wide dose range of 0.3 to 30 mg/kg, with no significant differences observed between male and female subjects.[2]

Toxicology studies in cynomolgus monkeys were crucial for establishing a preliminary safety margin. The highest non-severely toxic dose (HNSTD) was determined to be 30 mg/kg.[2] This finding was highly encouraging, as it suggested a wide therapeutic index, given that the anticipated therapeutic doses in humans were expected to be significantly lower. The eventual recommended Phase II dose (RP2D) in humans was established at 6.3 mg/kg, well below the HNSTD in NHPs, confirming the favorable safety margin predicted by these preclinical studies.[6] The deliberate and comprehensive nature of this preclinical program, particularly the testing in HER2-low models and the establishment of a wide therapeutic index, demonstrated a rational and well-executed development process that accurately forecasted the drug's promising clinical profile.

Comprehensive Clinical Development Program Overview

The clinical development of JSKN-003 is characterized by an aggressive and strategically parallel approach, aimed at rapidly establishing its efficacy in key indications while simultaneously pursuing global expansion. The program is built upon foundational Phase I/II studies in Australia and China, which have provided the data to launch multiple pivotal Phase III trials and explore novel combination therapies.

Foundational First-in-Human and Phase I/II Studies

The clinical journey of JSKN-003 began with two key early-phase trials designed to establish its safety, pharmacokinetics, and preliminary efficacy.

• JSKN003-101 (NCT05494918): This was the first-in-human, Phase I, open-label, dose-escalation study initiated in Australia. The trial enrolled patients with advanced, inoperable, or metastatic solid tumors confirmed to have HER2 expression (IHC $\ge1+$) or a HER2 mutation. Its primary goals were to evaluate safety and tolerability, define the dose-limiting toxicities (DLTs), and determine the maximum tolerated dose (MTD) and/or the recommended Phase II dose (RP2D). The study employed a sophisticated Bayesian Optimal Interval (BOIN) design to guide dose escalation, allowing for efficient and safe dose finding.[2]
• JSKN003-102 (NCT05744427): Conducted in China, this large Phase I/II study mirrored the objectives of the Australian trial but was designed with a broader scope. It included an initial dose-escalation phase followed by multiple cohort expansions to evaluate JSKN-003 in specific tumor types at the determined RP2D. This study has been a cornerstone of the development program, generating the majority of the publicly available efficacy and safety data for indications such as platinum-resistant ovarian cancer, breast cancer, and gastrointestinal cancers.[3]

Pivotal Phase III Trials

Based on the highly encouraging results from the Phase I/II program, Alphamab and its partners have launched an ambitious slate of Phase III trials in China to confirm the drug's efficacy and seek regulatory approval.

• JSKN003-306 (NCT06751485): This pivotal trial is a randomized, open-label, controlled study in patients with platinum-resistant ovarian cancer (PROC), primary peritoneal cancer, or fallopian tube cancer. It directly compares the efficacy and safety of JSKN-003 against the investigator's choice of standard-of-care single-agent chemotherapy (doxorubicin, paclitaxel, or topotecan). A critical feature of this trial is its "all-comers" design, enrolling patients regardless of their tumor's HER2 expression level, a strategy directly supported by the strong efficacy signals seen in HER2-negative patients in earlier studies. The primary endpoint is progression-free survival (PFS) as assessed by a Blinded Independent Review Committee (BIRC).[3]
• JSKN003-301 (NCT06846437): This trial represents a direct challenge to an established standard of care in HER2-positive breast cancer. It is a randomized, controlled, open-label study comparing JSKN-003 (administered at 6.3 mg/kg every three weeks) against the ADC ado-trastuzumab emtansine (T-DM1). The trial enrolls patients with unresectable locally advanced or metastatic HER2-positive breast cancer whose disease has progressed after prior treatment with trastuzumab and a taxane. The primary endpoint is also BIRC-assessed PFS, and a positive result would position JSKN-003 as a superior treatment option in this setting.[20]
• Phase III Trial in HER2-Low Breast Cancer: Multiple sources confirm that a third pivotal Phase III trial is actively enrolling patients in China for the treatment of HER2-low expressing breast cancer.[1] This trial is strategically aimed at capturing a large patient population where new targeted therapies have recently demonstrated significant benefit.

Global Expansion and New Formulations

The development strategy extends beyond China, with clear steps toward global registration and life-cycle management.

• JSKN003-202: Marking its entry into the United States, the FDA has approved the initiation of this randomized, open-label, multi-center Phase II clinical study. The trial will evaluate the safety and efficacy of JSKN-003 in patients with PROC and will help determine the recommended Phase III dose (RP3D) for a Western patient population, serving as a crucial bridge for global development.[6]
• JSKN033: Looking toward future therapeutic paradigms, Alphamab is developing JSKN033, a novel, first-in-class subcutaneous co-formulation of JSKN-003 with Envafolimab, a subcutaneously administered PD-L1 inhibitor.[1] This combination, currently in Phase I/II studies (NCT06770881, NCT06226766), aims to exploit the potential synergy between ADC-induced immunogenic cell death and immune checkpoint blockade, while offering the significant convenience of subcutaneous administration.

The confidence behind this rapid and parallel development strategy is palpable. Initiating three resource-intensive Phase III trials, including a head-to-head study against an established ADC, before the completion of formal Phase II studies, signals an exceptionally high degree of conviction in the drug's robust efficacy and safety profile observed in early trials. This assertive approach, coupled with simultaneous global expansion and forward-thinking life-cycle management, is designed to establish JSKN-003 as a best-in-class ADC across multiple major oncology indications as swiftly as possible.

Trial ID (NCT Number)	Phase	Indication(s)	Key Patient Population	Design	Comparator Arm	Primary Endpoint(s)	Status
JSKN003-101 (NCT05494918)	1	Advanced Solid Tumors	HER2-expressing (IHC $\ge1+$) or HER2-mutant	Open-label, Dose Escalation (BOIN)	None (Monotherapy)	Safety, Tolerability, MTD/RP2D	Completed
JSKN003-102 (NCT05744427)	1/2	Advanced Solid Tumors	HER2-expressing (IHC $\ge1+$) or HER2-mutant	Open-label, Dose Escalation & Expansion	None (Monotherapy)	Safety, Tolerability, Antitumor Activity	Active, Not Recruiting
JSKN003-306 (NCT06751485)	3	Platinum-Resistant Ovarian Cancer (PROC)	Platinum-resistant disease, regardless of HER2 expression	Randomized, Open-label, Controlled	Investigator's Choice Chemotherapy	PFS by BIRC	Recruiting
JSKN003-301 (NCT06846437)	3	HER2-Positive Breast Cancer	Unresectable locally advanced/metastatic, post-trastuzumab/taxane	Randomized, Open-label, Controlled	Ado-trastuzumab emtansine (T-DM1)	PFS by BIRC	Recruiting
JSKN003-202	2	Platinum-Resistant Ovarian Cancer (PROC)	Platinum-resistant disease	Randomized, Open-label, Multi-center	Not specified	Safety, Efficacy, RP3D	Approved to start
JSKN033 Program (e.g., NCT06770881)	1/2	Advanced Malignant Tumors	Advanced solid tumors	Open-label, Dose Escalation & Expansion	None (Combination)	Safety, Tolerability, Antitumor Activity	Recruiting

Clinical Efficacy in Platinum-Resistant Ovarian Cancer (PROC)

The clinical data for JSKN-003 in platinum-resistant ovarian cancer (PROC) represent one of the most significant breakthroughs in the drug's development program. The results from a pooled analysis of heavily pretreated patients have demonstrated a level of efficacy that substantially surpasses current standards of care and, most notably, have revealed a therapeutic benefit that extends beyond the traditional confines of HER2-positive disease.

Patient Population and Study Context

The primary efficacy data for JSKN-003 in this indication come from a pooled analysis of 46 patients with PROC who were enrolled in the Phase I JSKN003-101 (Australia) and Phase I/II JSKN003-102 (China) studies.[3] The clinical context of this patient population is critical for interpreting the results. These were patients with highly refractory disease, characterized by:

• Heavy Pretreatment: 65.2% of patients had received three or more prior lines of systemic therapy.
• Prior Standard Therapies: The majority had already been exposed to and progressed on modern standards of care, with 80.4% having received prior bevacizumab and 63.0% having received a prior PARP inhibitor.[3]

For such a patient population, the prognosis is exceptionally poor. Standard single-agent chemotherapy offers objective response rates in the range of 6%–13% and a median progression-free survival of only 3 to 4 months.[8] It is against this bleak backdrop that the efficacy of JSKN-003 must be evaluated.

Overall Efficacy in the Pooled PROC Cohort

The updated data presented at the 2025 ASCO Annual Meeting, with a data cut-off of November 29, 2024, and a median follow-up of 6.9 months, showed compelling anti-tumor activity in 45 efficacy-evaluable patients.[3] The key efficacy metrics were:

• Objective Response Rate (ORR): An ORR of 64.4% (95% CI: 48.8, 78.1) was achieved, a result that is five- to ten-fold higher than that expected from single-agent chemotherapy.
• Median Progression-Free Survival (PFS): The median PFS was 7.1 months (95% CI: 5.6, 9.7), representing a doubling of the survival time without disease progression compared to standard therapy.
• Overall Survival (OS): While OS data are still maturing, the 9-month OS rate was 84.9% (95% CI: 56.6, 95.4), an early but very encouraging signal of a survival benefit.

Landmark Efficacy Across HER2 Expression Subgroups

The most groundbreaking finding from the PROC cohort is the demonstration of JSKN-003's efficacy irrespective of the tumor's HER2 expression level, as determined by IHC.[3] This observation challenges the fundamental assumption that HER2-targeted ADCs are only effective in tumors with significant HER2 protein expression.

• HER2-expressing (IHC 1+/2+/3+): In the 39.1% of patients whose tumors had some level of HER2 expression, the efficacy was particularly pronounced, with an ORR of 72.2% and a median PFS of 9.4 months.[3]
• HER2-no-expressing (IHC 0): Remarkably, in the 45.7% of patients whose tumors were classified as HER2-negative, JSKN-003 still demonstrated substantial clinical benefit. The ORR in this subgroup was 55.0%, with a median PFS of 5.6 months.[3] Later data cuts have continued to support this finding, reporting an ORR of 52.4% and a median PFS of 6.6 months in the IHC 0 group.[10]

This high level of activity in HER2-negative tumors cannot be explained by direct target engagement on every cancer cell. It provides the strongest clinical validation to date for the potency of JSKN-003's bystander effect. The data strongly suggest that even minimal, perhaps undetectable, levels of HER2 on a fraction of tumor cells are sufficient for the ADC to gain entry, after which the membrane-permeable payload is released to kill surrounding HER2-negative cells. This mechanism effectively uncouples the drug's efficacy from the requirement of high, uniform biomarker expression, a limitation that has constrained many other targeted therapies. This finding is the cornerstone of the "all-comers" enrollment strategy for the pivotal Phase III JSKN003-306 trial, which is now significantly de-risked by this robust early-phase data.

Efficacy Metric	Overall Population (n=45)	HER2-Expressing (IHC 1+/2+/3+) (n=18)	HER2-Negative (IHC 0) (n=20)
Objective Response Rate (ORR)	64.4%	72.2%	55.0%
Median Progression-Free Survival (PFS)	7.1 months	9.4 months	5.6 months
9-month Overall Survival (OS) Rate	84.9%	83.0%	100.0%
Data from pooled analysis of NCT05494918 and NCT05744427 as of Nov 29, 2024.3

Efficacy in Primary Platinum-Refractory Ovarian Cancer

Further underscoring its potency, JSKN-003 was evaluated in a subset of 26 patients with primary platinum-refractory disease—defined as progression within three months of completing first-line platinum-based chemotherapy.[28] This population represents the most aggressive and chemo-resistant form of ovarian cancer, with extremely limited treatment options. Even in this exceptionally challenging setting, JSKN-003 demonstrated meaningful clinical activity, achieving an ORR of 32.0%, a disease control rate (DCR) of 72.0%, and a median PFS of 4.1 months.[28] These results provide new hope for a patient population that has historically been excluded from most clinical trials due to their poor prognosis.

Clinical Efficacy in HER2-Positive and HER2-Low Breast Cancer

In the competitive landscape of HER2-targeted therapies for breast cancer, JSKN-003 has demonstrated a compelling efficacy profile in heavily pretreated patients. The clinical development strategy is twofold: to establish superiority over existing standards of care in HER2-positive disease and to address the significant emerging challenge of resistance to newer ADCs, while also expanding into the large HER2-low patient population.

Patient Population and Study Context

The efficacy data in breast cancer are derived from a pooled analysis of patients with HER2-positive (defined as IHC 3+ or IHC 2+/ISH+) advanced disease from the JSKN003-101 and JSKN003-102 trials. As of November 2024, this cohort included 71 patients, later expanding to 88 patients by February 2025.[4] This was a population with advanced, refractory disease, characterized by:

• Extensive Prior Therapy: All patients had received prior anti-HER2 therapy, with 56.3% having received three or more prior lines of treatment.
• Prior ADC Exposure: A vast majority (87.3%) had been treated with prior ADCs or tyrosine kinase inhibitors (TKIs), indicating a population with multiple mechanisms of resistance.[4]

Efficacy in T-DXd-Naïve Patients

For patients with HER2-positive breast cancer who had not yet been exposed to trastuzumab deruxtecan (T-DXd), JSKN-003 showed robust and consistent anti-tumor activity.

• In an analysis of 56 evaluable patients, the ORR was 67.9% and the disease control rate (DCR) was 94.6%.[4]
• Efficacy appeared to be dose-dependent, with the ORR reaching 70.0% in the subgroup of patients treated at the recommended Phase II dose (RP2D) of 6.3 mg/kg.[4]
• A later analysis with more patients (75 evaluable) reported a confirmed ORR of 54.7% overall, which rose to 73.3% in the cohort receiving the 6.3 mg/kg RP2D.[10] These high response rates in a pretreated population are the basis for the pivotal Phase III trial (NCT06846437) directly comparing JSKN-003 to the established second-line standard of care, T-DM1.

Efficacy in T-DXd-Experienced Patients

A critical challenge in modern HER2-positive breast cancer treatment is the development of resistance to T-DXd. There is currently no established standard of care for patients whose disease progresses on this highly active agent. Early data for JSKN-003 in this setting are therefore of immense clinical interest. In a small cohort of six patients with prior T-DXd exposure, JSKN-003 demonstrated clear signs of clinical activity: one patient achieved a partial response (PR) and three others had stable disease (SD), with tumor shrinkage observed in three of the six patients.[4]

While this dataset is small, it provides the first clinical evidence that JSKN-003 may be able to overcome resistance to another HER2-targeted TOPIi-based ADC. This potential activity could be attributed to JSKN-003's distinct molecular features, such as its biparatopic antibody leading to more efficient internalization or its unique conjugation chemistry affecting payload delivery and retention. If confirmed in larger studies, this would position JSKN-003 as a vital new therapeutic option for a rapidly growing patient population with no effective treatments.

Patient Subgroup	N (evaluable)	Objective Response Rate (ORR)	Disease Control Rate (DCR)
Overall T-DXd Naïve	56	67.9%	94.6%
T-DXd Naïve at RP2D (6.3 mg/kg)	30	70.0%	Not Reported
T-DXd Experienced	6	16.7% (1 PR)	66.7% (1 PR + 3 SD)
Data from pooled analysis as of Nov 29, 2024.4

Efficacy in HER2-Low Breast Cancer

Mirroring the successful strategy of other next-generation ADCs, Alphamab is actively developing JSKN-003 for the HER2-low breast cancer population (IHC 1+ or IHC 2+/ISH-negative). This represents a much larger patient segment than the traditionally defined HER2-positive group. Early signals of efficacy have been positive. Data from the dose-escalation phase of the Australian JSKN003-101 study showed an ORR of 40.0% in a cohort of 10 patients with HER2-low disease.[13] Based on this promising preliminary activity, a dedicated Phase III trial for HER2-low breast cancer is now underway in China, positioning JSKN-003 to compete in this highly valuable market segment.[1]

Emerging Efficacy in Gastrointestinal and Other Solid Tumors

Beyond its lead indications in ovarian and breast cancer, JSKN-003 has demonstrated promising early efficacy signals across a range of other HER2-expressing solid tumors, particularly in gastrointestinal (GI) malignancies. These findings highlight the drug's potential for broader, pan-tumor utility and have already led to accelerated regulatory pathways for these indications.

HER2-Positive Gastric/Gastroesophageal Junction (GC/GEJ) Cancer

HER2 amplification is a known driver in a subset of gastric and gastroesophageal junction cancers. In patients with heavily pretreated, HER2-positive (IHC 3+) GC/GEJ, JSKN-003 has shown remarkable activity.

• Initial reports from the Phase I/II JSKN003-102 study showed ORRs of 80% to 100% in small cohorts of 4 to 5 patients.[5]
• A larger pooled analysis presented in 2025, including 27 patients with GC/GEJ, confirmed this strong signal, reporting an ORR of 63.0% and a DCR of 92.6%. The median PFS in this population was 9.6 months.10 These results are particularly encouraging in a disease setting where outcomes after first-line therapy are poor. In recognition of this high unmet need and the promising data, the U.S. FDA granted JSKN-003 an Orphan Drug Designation for the treatment of GC/GEJ in July 2025.6

HER2-Positive Colorectal Cancer (CRC)

The efficacy signals in HER2-positive metastatic colorectal cancer (mCRC) are among the most impressive in the JSKN-003 development program to date. For patients with HER2-positive mCRC who have failed standard chemotherapies (oxaliplatin, fluorouracil, and irinotecan), current approved therapies offer very limited benefit, with a median PFS of only 2.0 to 3.7 months.[9]

• In a pooled analysis of 21 patients with HER2-positive (IHC 3+) mCRC, JSKN-003 achieved an ORR of 61.9% and a DCR of 95.2%.[10]
• Most strikingly, the median PFS reached 13.8 months.10 This represents a nearly four- to seven-fold improvement over existing treatment options and signals a potentially practice-changing therapy for this population. The strength of this data was validated by China's NMPA, which granted JSKN-003 a Breakthrough Therapy Designation for this specific indication, a move expected to significantly accelerate its development and review process.9

Pan-Tumor Potential

The foundational dose-escalation trials (JSKN003-101 and JSKN003-102) enrolled patients with a wide variety of advanced solid tumors, including bladder cancer, esophageal cancer, and non-small cell lung cancer.[5] The observation of responses across these different histologies suggests that the efficacy of JSKN-003 is driven primarily by the presence of the HER2 target rather than the tumor's tissue of origin. This supports the potential for a "pan-tumor" or "tumor-agnostic" development path for JSKN-003 in any solid tumor that expresses HER2, which could further broaden its clinical utility in the future.

Safety, Tolerability, and Pharmacokinetic Profile in Human Trials

A comprehensive analysis of the safety and pharmacokinetic data from the early-phase clinical trials reveals that JSKN-003 possesses a manageable and predictable safety profile, a key attribute for any successful ADC. The toxicities observed are consistent with the mechanism of action of a topoisomerase I inhibitor payload but appear to be less severe than those associated with some competitor ADCs, potentially providing a significant clinical advantage.

Overall Safety Summary

Across multiple studies and patient populations, JSKN-003 has been well-tolerated.[3] The incidence of severe, Grade $\ge3$ treatment-related adverse events (TRAEs) has been consistently low, generally ranging from 11% to 20% of patients depending on the cohort and duration of follow-up.[3] Furthermore, a critical indicator of tolerability is the rate of treatment discontinuation due to toxicity. For JSKN-003, TRAEs leading to treatment cessation or death have been reported as either rare or non-existent in the available clinical trial summaries, suggesting that most adverse events can be effectively managed with supportive care or dose modifications.[3]

Common Adverse Events

The most frequently reported TRAEs are primarily low-grade (Grade 1-2) and are consistent with the known side effects of topoisomerase I inhibitors. These include:

• Gastrointestinal Toxicities: Nausea, diarrhea, vomiting, and decreased appetite are the most common adverse events observed across all studies.[3]
• Hematological Toxicities: Decreased white blood cell count, neutropenia, and anemia are also frequently reported, though severe instances are uncommon.[4]
• Constitutional Symptoms: Fatigue is a common, generally low-grade side effect.[4]

Adverse Events of Special Interest for ADCs

For ADCs carrying a TOPIi payload, certain toxicities require special attention due to their potential for severity. The profile of JSKN-003 in this regard appears favorable.

• Interstitial Lung Disease (ILD)/Pneumonitis: This is a serious and potentially fatal toxicity associated with other ADCs in this class, such as T-DXd. For JSKN-003, the reported incidence of ILD has been relatively low and the severity generally mild. Across the PROC, breast, and GI cancer cohorts, the rate of any-grade ILD has ranged from approximately 4% to 9%.[3] Crucially, the vast majority of these cases have been Grade 1 or 2, with only a single Grade 3 event reported in the breast cancer cohort and no Grade 4 or 5 events mentioned in the available data.[3] This lower incidence and severity of ILD compared to historical data for T-DXd could represent a major competitive advantage in safety.
• Hematological Toxicity: While low-grade cytopenias are common, the rate of severe, Grade $\ge3$ events like neutropenia and lymphopenia has been low, reported at 4.3% each in one Phase I analysis.[5] This suggests a lower risk of myelosuppression compared to some cytotoxic agents.

Adverse Event	Any Grade (%)	Grade ≥3 (%)
Gastrointestinal
Nausea	32.6 - 50.0	~2.2
Diarrhea	37.0 - 62.5	~2.2
Vomiting	~26.1	~2.2
Decreased Appetite	~17.4	Not Reported
Hematological
Neutropenia / Neutrophil Count Decreased	~21.7	4.3 - 6.5
Anemia	~26.1	< 2.0
Thrombocytopenia / Platelet Count Decreased	~19.6	< 2.0
Constitutional
Fatigue	>20.0	~6.3
Adverse Event of Special Interest
Interstitial Lung Disease (ILD) / Pneumonitis	4.2 - 8.7	< 2.5 (one G3 case reported)
Data compiled from safety reports across Phase I/II studies.3 Ranges reflect different patient cohorts and data cut-offs.

Human Pharmacokinetics

Pharmacokinetic analyses from the Phase I studies have confirmed that JSKN-003 behaves predictably in humans. Following intravenous administration, drug exposure, as measured by maximum concentration ($C_{max}$) and area under the curve (AUC), increases proportionally with the dose in the therapeutic range of 4.2 mg/kg to 8.4 mg/kg, indicating linear pharmacokinetics.[5] The elimination half-life ($T_{1/2}$) is approximately 3 to 6 days, which is suitable for an every-three-week (Q3W) dosing schedule.[5] Importantly, no significant drug accumulation was observed after multiple dosing cycles, and the systemic exposure to the free, unconjugated payload was confirmed to be very low. This latter finding provides clinical validation for the high stability of the ADC in circulation, a key design feature intended to minimize off-target toxicity.[5]

Regulatory Landscape and Strategic Development Pathway

The clinical development of JSKN-003 is supported by a series of significant and positive interactions with major global regulatory agencies. The granting of multiple accelerated review designations serves as a powerful validation of the drug's promising clinical data and its potential to address areas of high unmet medical need. These regulatory milestones, combined with a key strategic partnership, have created a clear and expedited pathway toward potential commercialization.

China (NMPA/CDE)

The Center for Drug Evaluation (CDE) of China's NMPA has recognized the potential of JSKN-003 with two separate Breakthrough Therapy Designations (BTDs). A BTD is intended to expedite the development and review of drugs for serious conditions where preliminary clinical evidence indicates substantial improvement over available therapies.

• BTD for Platinum-Resistant Ovarian Cancer (PROC): In March 2025, JSKN-003 was granted a BTD for the treatment of PROC, primary peritoneal cancer, or fallopian tube cancer. Critically, the designation was explicitly granted for use in patients not restricted to HER2 expression levels.[7] This is a highly significant endorsement from the regulator, acknowledging the novel bystander-driven mechanism and its applicability to a broad, biomarker-unselected patient population.
• BTD for Colorectal Cancer (CRC): Subsequently, JSKN-003 received a second BTD for its use as a monotherapy in patients with HER2-positive advanced CRC who have failed prior treatment with standard chemotherapy regimens (oxaliplatin, fluorouracil, and irinotecan).[9] This designation was based on the exceptionally strong efficacy data observed in this setting.

United States (FDA)

The U.S. FDA has also provided key designations and approvals that pave the way for JSKN-003's development and potential marketing in the United States.

• Orphan Drug Designation (ODD): In July 2025, the FDA granted JSKN-003 an ODD for the treatment of gastric cancer and gastroesophageal junction (GC/GEJ) cancer.[6] This designation is for drugs intended to treat rare diseases (affecting fewer than 200,000 people in the U.S.) and provides significant incentives, including potential market exclusivity for seven years upon approval, tax credits for clinical trials, and waiver of prescription drug user fees.
• Investigational New Drug (IND) Approval: The FDA has cleared the IND application for JSKN-003, allowing Alphamab to initiate the Phase II clinical trial JSKN003-202 in the U.S. for patients with PROC.[6] This marks the formal commencement of its clinical evaluation in a U.S. patient population and is a critical step toward global registration.

Commercial and Licensing Strategy

Alphamab Oncology, the drug's originator, has executed a strategic partnership to accelerate its development and commercialization in the sizable Chinese market. In September 2024, Alphamab entered into a licensing agreement with JMT-Bio Technology Co., Ltd., a subsidiary of the major Chinese pharmaceutical firm CSPC Pharmaceutical Group.[7] Under the terms of the agreement, JMT-Bio was granted exclusive rights to develop and commercialize JSKN-003 for tumor-related indications in mainland China. This partnership provides Alphamab with significant upfront and potential milestone payments, while leveraging CSPC's extensive clinical development and commercial infrastructure to maximize the drug's reach in China. Alphamab judiciously retains the sole right to manufacture and supply JSKN-003, ensuring quality control and a continued revenue stream.[7]

Competitive Positioning and Future Perspectives

JSKN-003 is entering a dynamic and competitive therapeutic landscape, particularly in the arena of HER2-targeted therapies. Its unique molecular design and compelling clinical data position it not merely as another entrant but as a potential best-in-class agent with the ability to displace existing standards of care, address emerging resistance, and create entirely new treatment paradigms.

Competitive Landscape Analysis

The positioning of JSKN-003 must be assessed relative to the key incumbent and emerging therapies in its lead indications.

• Versus Ado-trastuzumab emtansine (T-DM1; Kadcyla): In the second-line setting for HER2-positive breast cancer, T-DM1 has long been the standard of care. The ongoing Phase III JSKN003-301 trial (NCT06846437) is a direct head-to-head comparison designed to prove superiority.[20] JSKN-003's potential advantages lie in its more potent topoisomerase I inhibitor payload compared to T-DM1's microtubule inhibitor (DM1) and its biparatopic antibody, which may lead to superior efficacy. A positive outcome in this trial would unequivocally position JSKN-003 as the new standard in this setting.
• Versus Trastuzumab deruxtecan (T-DXd; Enhertu): T-DXd is the most formidable competitor, having revolutionized the treatment of both HER2-positive and HER2-low breast cancer. JSKN-003 will compete with T-DXd across multiple fronts. The primary competitive angle for JSKN-003 will likely be its differentiated safety profile. The consistently lower rates of any-grade and severe interstitial lung disease (ILD) reported for JSKN-003 could be a decisive factor for clinicians weighing the risks and benefits for their patients.[3] Furthermore, the early but promising data showing JSKN-003's activity in patients who have progressed on T-DXd suggests it may have a unique role in overcoming resistance, potentially establishing a new line of therapy where none currently exists.[4]
• In Platinum-Resistant Ovarian Cancer (PROC): In this indication, JSKN-003 is not just competing—it is creating a new market. While other ADCs are approved or in development for specific subsets of PROC (e.g., mirvetuximab soravtansine for folate receptor alpha-positive patients), JSKN-003's demonstrated efficacy in an "all-comers" population, including HER2-negative patients, gives it a uniquely broad potential label.[3] It has the potential to become a foundational therapy for a wide swath of the PROC population, largely unopposed by other HER2-targeted agents.

Future Development and Unanswered Questions

While the current data are robust, several key areas of future development will be critical to defining the ultimate impact of JSKN-003.

• Combination Therapies: The JSKN033 program, which co-formulates JSKN-003 with the PD-L1 inhibitor Envafolimab, is a strategically vital next step.[1] The scientific rationale is that ADC-mediated tumor cell killing can release tumor antigens and create an inflamed microenvironment (immunogenic cell death), thereby priming the tumor for a more robust response to immune checkpoint blockade. The development of a subcutaneous co-formulation would also offer a major advantage in convenience and patient compliance, potentially making it a highly attractive combination regimen.[1]
• Central Nervous System (CNS) Activity: Brain metastases remain a major cause of morbidity and mortality in patients with HER2-positive breast cancer. The ability of an ADC to cross the blood-brain barrier and control CNS disease is a highly desirable attribute. Current Phase III protocols for JSKN-003 allow for the inclusion of patients with stable, treated brain metastases.[20] Future data readouts from these trials must be closely monitored for any signals of intracranial activity, as this would represent another significant clinical advantage.
• Optimal Sequencing: The emergence of multiple, highly active ADCs raises complex questions about their optimal sequencing. The data suggesting JSKN-003 works after T-DXd is a critical first step. However, larger, well-controlled studies will be needed to definitively establish the best treatment sequence to maximize long-term outcomes for patients.

Final Synthesis and Strategic Outlook

JSKN-003 is more than an incremental advance in ADC technology; it is a rationally designed therapeutic with a demonstrated ability to challenge existing treatment paradigms. Its clinical success is built on a foundation of superior molecular engineering that translates into a potent, HER2-agnostic bystander effect. The strategic vision for JSKN-003 is clear and multi-faceted: first, to displace older standards of care in established biomarker-defined populations (vs. T-DM1 in HER2+ breast cancer); second, to address the most pressing clinical gaps created by newer therapies, such as T-DXd resistance and safety concerns; and third, to create new, biomarker-agnostic markets where none previously existed (all-comer PROC). The successful execution of its ambitious pivotal trial program and the continued maturation of its favorable safety database will be the final determinants of its role, but all current evidence points to JSKN-003 becoming a cornerstone therapy in the treatment of a wide range of solid tumors.

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