IMAB027 (ASP1650): A Comprehensive Report on a Claudin 6-Targeting Monoclonal Antibody

I. Introduction to IMAB027

A. Overview and Identification

IMAB027 is an investigational monoclonal antibody (mAb) specifically developed to target Claudin 6 (CLDN6), a protein that shows aberrant expression in a variety of human cancers.[1] This therapeutic agent is also widely recognized by the synonym ASP1650, particularly in documentation related to its development by Astellas Pharma.[1] The DrugBank identification number assigned to IMAB027 is DB17282, indicating its status as a cataloged investigational drug.

As a biopharmaceutical product, IMAB027 falls under the category of biotech drugs, leveraging biological systems for its production and therapeutic effect. The molecular weight of this antibody is approximately 144.42 kDa [1], typical for an IgG class monoclonal antibody. The Chemical Abstracts Service (CAS) Registry Number for IMAB027 is 1650599-68-0.[1]

The dual nomenclature, IMAB027 and ASP1650, is indicative of its developmental history. "IMAB" likely stems from Ganymed Pharmaceuticals' "Ideal Monoclonal Antibody" platform, the originating company, while "ASP" is a common prefix for compounds developed by Astellas Pharma. This naming pattern often signifies a transition in the drug's development, such as a partnership or acquisition, which in this case was the acquisition of Ganymed by Astellas.[2] The assignment of a DrugBank ID suggests that IMAB027 has undergone significant preclinical characterization and has progressed into clinical investigation.

B. Classification and Antibody Type

IMAB027 is classified therapeutically as an antineoplastic agent and an immunotherapy, functioning as a monoclonal antibody.[2] The initial query and several sources describe IMAB027 as a chimeric monoclonal antibody.[1] Specifically, MedChemExpress details IMAB027 (ASP1650) as being of "Chimeric" species origin with a "Human IgG1 kappa" isotype.[1]

However, a nuanced picture emerges when considering its application in antibody-drug conjugates (ADCs). Several sources discussing ADCs derived from an anti-CLDN6 antibody, such as CLDN6-23-ADC or IMAB027-vcMMAE, refer to the antibody component as "fully humanized".[7] This apparent discrepancy likely reflects an evolutionary step in the antibody's engineering. It is common practice in therapeutic antibody development for an initial chimeric construct to be further refined into a humanized version. Humanization aims to reduce the immunogenicity of the antibody in patients, thereby improving its safety profile and allowing for repeated dosing, which is particularly crucial for more complex therapeutics like ADCs. Thus, the naked antibody IMAB027/ASP1650, as investigated in early clinical trials, was likely chimeric, while a humanized version was subsequently developed or selected for the construction of ADCs to optimize therapeutic performance.

C. Originator and Developers

The originator of IMAB027 is Ganymed Pharmaceuticals AG, a company focused on developing novel cancer immunotherapies.[2] Subsequent development involved Astellas Pharma, following its acquisition of Ganymed Pharmaceuticals, a transaction finalized in December 2016.[2]

Astellas' acquisition of Ganymed was largely publicized due to the lead asset IMAB362 (zolbetuximab), an antibody targeting Claudin 18.2.[9] While IMAB027 was a part of Ganymed's pipeline and progressed to clinical trials under Astellas (as ASP1650), its visibility in Astellas' more recent public pipeline disclosures has diminished. Astellas' oncology pipeline updates for Fiscal Year 2024 (as of April 2025) prominently feature programs like zolbetuximab but do not explicitly list IMAB027/ASP1650 as an active monotherapy program.[15] This, combined with the completion of the Phase II trial for ASP1650 (NCT03760081) in October 2020 [19], may suggest a deprioritization or discontinuation of IMAB027 development as a standalone naked antibody by Astellas. Nevertheless, the target antigen, CLDN6, remains an area of active investigation in the oncology field, with other entities pursuing CLDN6-targeted therapies, including ADCs.[20]

Table I: Summary of IMAB027 Key Characteristics

Parameter	Description	Source(s)
Primary Name	IMAB027	User Query
DrugBank ID	DB17282	User Query
Alternative Names	ASP1650	1
CAS Number	1650599-68-0	1
Type	Biotech (Monoclonal Antibody)	User Query
Original Isotype/Species (IMAB027/ASP1650)	Human IgG1 kappa / Chimeric	1
Reported Isotype/Species (for ADC component)	Humanized IgG1	7
Target Antigen	Claudin 6 (CLDN6)	1
Originator	Ganymed Pharmaceuticals AG	2
Developer(s)	Ganymed Pharmaceuticals AG, Astellas Pharma	2
Primary Therapeutic Area	Oncology	2
Approximate Molecular Weight	144.42 kDa	1

II. The Target: Claudin 6 (CLDN6)

A. Biological Role of Claudins and CLDN6

Claudins are a family of integral transmembrane proteins, comprising more than 20 members, that represent the primary structural and functional components of tight junctions (TJs) in epithelial and endothelial cell layers.[8] TJs are crucial intercellular adhesion complexes that regulate paracellular permeability (the flow of ions and solutes through the space between cells) and are essential for maintaining cell polarity and tissue barrier integrity.

CLDN6, a specific member of this family, is directly involved in these cell-cell adhesion processes and contributes to the formation and stability of TJs.[23] Like other claudins, CLDN6 features four transmembrane domains, two extracellular loops, and cytoplasmic N- and C-termini. The C-terminal tail often contains a PDZ-binding motif, enabling interaction with various scaffolding and signaling proteins, thereby linking TJs to intracellular signaling pathways and the cytoskeleton.[20] Beyond its structural role, CLDN6 has been reported to be unique among claudins in its potential to specifically activate cell adhesion signals and modulate the activity of nuclear receptors.[20] This suggests a more complex role for CLDN6, extending beyond simple barrier function to include participation in cell signaling and regulation of gene expression, which could influence cell proliferation and differentiation processes.[20] The aberrant expression or function of CLDN6 in cancer cells could therefore contribute to malignant phenotypes not only through altered cell adhesion but also via dysregulated intracellular signaling.

B. CLDN6 Expression Profile: Oncofetal Antigen Characteristics

The therapeutic interest in CLDN6 is largely driven by its highly restricted and differential expression pattern, categorizing it as an oncofetal antigen.

• Expression in Cancer Tissues: CLDN6 is frequently and aberrantly re-expressed at high levels in a wide array of human solid tumors. These include ovarian cancer (found in over 55% of cases [25] and specifically in 29% of epithelial ovarian carcinomas [14]), testicular cancer (particularly germ cell tumors), uterine cancer, lung cancer (notably non-small cell lung cancer - NSCLC), endometrial cancer, gastric cancer, gastroesophageal junction (GEJ) adenocarcinoma, pancreatic cancer, and breast cancer.[1] Some pediatric solid tumors, such as desmoplastic small round cell tumors and germ cell tumors, also exhibit strong and homogeneous CLDN6 expression.[15] In certain malignancies, elevated CLDN6 expression has been linked to a poorer prognosis.[20]
• Expression in Normal Adult Tissues: In stark contrast to its prevalence in tumors, CLDN6 expression is virtually absent or detected at extremely low levels in most healthy adult tissues.[12] This highly restricted expression in normal adult physiology is a critical attribute that makes CLDN6 an attractive target for cancer therapy.
• Expression in Fetal Tissues: CLDN6 is physiologically expressed during embryonic and fetal development.[5] Its expression is primarily observed in the epithelial cells of various developing organs, including the skin, lungs, kidneys, intestinal tract, and pancreas. Notably, it is generally not found in undifferentiated blastemal cells. Following birth, the expression of CLDN6 in these epithelial progenitor populations is significantly downregulated, and it largely disappears from terminally differentiated adult epithelia, typically within a few weeks postnatally.[15]

This oncofetal expression pattern—high during fetal development and in cancerous tissues, but minimal in normal adult tissues—is of paramount importance for targeted therapy. It suggests that CLDN6-directed treatments could selectively attack cancer cells while largely sparing healthy adult cells, potentially leading to a wider therapeutic window and reduced on-target, off-tumor toxicities. The re-expression of such embryonic antigens in tumors is a well-recognized phenomenon in oncology, often associated with cellular de-differentiation, aberrant activation of developmental pathways, and the uncontrolled proliferative state characteristic of cancer.

C. CLDN6 as a Therapeutic Target in Oncology

The unique oncofetal expression signature of CLDN6 has rendered it a highly promising target for the development of various cancer immunotherapies. The stark contrast between its high expression on tumor cells and its near absence on normal adult cells provides a strong rationale for its selection. Therapeutic modalities being explored against CLDN6 include:

• Naked Monoclonal Antibodies: Such as IMAB027 (ASP1650), designed to elicit immune-mediated killing of CLDN6-positive tumor cells.[4]
• Antibody-Drug Conjugates (ADCs): These agents combine the specificity of an anti-CLDN6 antibody with the potent cell-killing activity of a conjugated cytotoxic payload. Examples include IMAB027-vcMMAE (ASP1650 conjugated to monomethyl auristatin E) [8], as well as other investigational ADCs like DS-9606 and TORL-1-23.[20]
• CAR T-Cell Therapies: Genetically engineered T-cells expressing a chimeric antigen receptor (CAR) that recognizes CLDN6 are being developed. An example is BNT211, which is being investigated in combination with a CLDN6-encoding mRNA vaccine (CARVac) designed to enhance CAR T-cell persistence and activity.[15]

The frequent expression of CLDN6 in cancers with high unmet medical needs, such as platinum-resistant ovarian cancer and refractory germ cell tumors, further amplifies its clinical relevance.[3] The pursuit of CLDN6 by multiple entities using these diverse therapeutic strategies underscores strong confidence in its potential as a valuable target. Moreover, the expression of CLDN6 on tumor tissue is increasingly used as a predictive biomarker to select patients for clinical trials of CLDN6-targeted agents, aiming to enrich for populations most likely to respond.[20]

Table II: Overview of Claudin 6 Expression in Malignant and Normal Tissues

Tissue Category	CLDN6 Expression Level	Specific Examples/Notes	Key Source(s)
Cancer Tissues	High / Aberrant	Ovarian cancer, testicular germ cell tumors, endometrial cancer, non-small cell lung cancer (NSCLC), gastric/GEJ adenocarcinoma, pancreatic cancer, desmoplastic small round cell tumors. Expression can be associated with poor prognosis.	1
Normal Adult Tissues	Very Low / Absent	Generally absent or expressed at very low levels in healthy adult tissues, providing a basis for tumor selectivity.	12
Fetal Tissues	Physiologically High during embryonic development	Expressed in epithelial cells of developing organs such as skin, lungs, kidneys, intestinal tract, and pancreas. Expression is significantly downregulated and largely disappears within weeks after birth in terminally differentiated epithelia.	5

III. IMAB027: Mechanism of Action

A. Binding Specificity to CLDN6

IMAB027 (ASP1650) is a monoclonal antibody engineered to recognize and bind with high specificity to extracellular epitopes of human Claudin 6 (CLDN6).[1] A crucial characteristic for its therapeutic potential is its selectivity for CLDN6 over other structurally related members of the claudin protein family. Preclinical studies have confirmed that IMAB027 binds specifically to CLDN6 and does not exhibit significant cross-reactivity with other closely related claudins, such as CLDN3, CLDN4, and CLDN9.[1] This high degree of specificity is vital for minimizing off-target binding to other claudins that may be expressed on normal, healthy tissues, thereby reducing the risk of unintended side effects. The binding affinity of IMAB027 to CLDN6 has been quantified, with an EC50​ (half-maximal effective concentration) value of 2.295 ng/mL reported for its binding to immobilized human Claudin-6/CLDN6 Protein-Virus-Like Particles (VLPs).[1]

The claudin family is extensive, and its members share considerable structural homology. However, their expression patterns in normal adult tissues can vary significantly. For instance, CLDN3 and CLDN4 have different tissue distribution profiles compared to the oncofetal pattern of CLDN6. Therefore, the demonstrated ability of IMAB027 to discriminate between CLDN6 and these other claudins is a key attribute. This selectivity is fundamental to achieving a favorable therapeutic index, ensuring that the antibody's biological effects are predominantly localized to CLDN6-expressing cancer cells.

B. Immunological Effector Functions

Upon binding to CLDN6 on the surface of cancer cells, IMAB027, being an IgG1 kappa antibody, is designed to mediate tumor cell killing primarily through the engagement of the host's immune system. The principal effector functions attributed to IMAB027 include:

• Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC): IMAB027 can trigger ADCC, a process wherein the Fc region of the antibody binds to Fc receptors (specifically FcγRIIIa or CD16a) on immune effector cells, primarily Natural Killer (NK) cells. This engagement activates the NK cells to release cytotoxic granules (containing perforin and granzymes) that induce apoptosis in the CLDN6-expressing target tumor cell. In vitro studies have consistently shown that IMAB027 induces target-selective ADCC against CLDN6-positive ovarian and testicular cancer cell lines.[1] The potency of this effect is highlighted by median EC50​ values in the ng/mL range.[27] Recognizing the importance of this mechanism, an ADCC-enhanced version of IMAB027 has also been developed using Creative Biolabs' Afuco™ platform.[12] This platform typically involves producing afucosylated antibodies, which exhibit increased affinity for FcγRIIIa, leading to more potent ADCC activity.
• Complement-Dependent Cytotoxicity (CDC): IMAB027 can also activate the classical complement pathway. Binding of the antibody to CLDN6 on the tumor cell surface allows the C1q component of the complement system to bind to the Fc region of IMAB027. This initiates a proteolytic cascade that culminates in the formation of the Membrane Attack Complex (MAC) on the target cell membrane, leading to osmotic lysis and cell death. CDC induction by IMAB027 has been demonstrated in vitro using CLDN6-expressing cancer cell lines, also with median EC50​ values in the ng/mL range.[1]
• Induction of Apoptosis (as a Naked Antibody): There is some discrepancy in the literature regarding the ability of naked IMAB027 to directly induce apoptosis. Commercial suppliers like MedChemExpress state that IMAB027 induces apoptosis in CLDN6+ ovarian and testicular cancer cell lines.[1] However, a detailed preclinical characterization by Türeci et al., who were involved in the antibody's development, reported that "Direct induction of apoptosis did not appear to be a contributor to the antitumor effect of IMAB027".[27] Given that primary research from developers often provides more nuanced mechanistic details, it is likely that direct apoptosis induction is not a major primary mechanism of action for the unconjugated antibody. Instead, apoptosis observed in some contexts might be a downstream consequence of ADCC or CDC.

The collective evidence strongly suggests that the primary antitumor mechanisms of naked IMAB027 are immune-mediated, relying on ADCC and CDC to eliminate CLDN6-positive cancer cells. The focus on developing ADCC-enhanced versions further emphasizes the significance of this effector pathway for the antibody's therapeutic activity.

C. Context within Ganymed's Ideal Monoclonal Antibody (IMAB) Platform

IMAB027 was conceived and developed as part of Ganymed Pharmaceuticals' "Ideal Monoclonal Antibody" (IMABs) platform.[3] The central tenet of the IMAB platform was the identification and targeting of antigens that exhibit exceptionally high expression on tumor cells with minimal or no expression on normal, healthy adult cells. This strategy was aimed at maximizing the therapeutic index by enabling potent on-target tumor cell killing while significantly reducing the risk of off-tumor toxicities, thereby creating a broad therapeutic window.[9]

Claudin 6, with its distinct oncofetal expression profile—being prevalent in numerous cancers and embryonic tissues but largely absent from healthy adult tissues—fit perfectly with the "ideal target" criteria defined by this platform. IMAB027 was the second antibody from Ganymed's IMAB platform to progress into clinical trials, following IMAB362 (zolbetuximab), which targets CLDN18.2.[26] The development of IMAB027 against CLDN6, therefore, directly reflects the core philosophy of the IMAB platform. The clinical evaluation of IMAB027 provides a practical assessment of this "ideal target" strategy, offering insights into both the potential and the challenges of translating such a targeted approach into tangible clinical benefits for cancer patients. Even if the monotherapy efficacy of IMAB027 proved limited in some settings, the platform's rationale for selecting highly tumor-specific targets like CLDN6 remains valid for guiding the development of other therapeutic modalities, such as ADCs or CAR T-cell therapies.

IV. Preclinical Development of IMAB027 (Naked Antibody)

A. In Vitro Studies

The preclinical evaluation of IMAB027 involved a comprehensive suite of in vitro experiments to characterize its binding properties and anti-tumor activity.

• Binding and Specificity: As previously noted, IMAB027 demonstrated highly specific binding to cells expressing CLDN6. Importantly, this binding was selective, with no significant cross-reactivity observed with other closely related claudin family members, including CLDN3, CLDN4, and CLDN9.[1] This specificity is crucial for a targeted therapy.
• Cytotoxicity via Immune Effector Mechanisms: IMAB027 effectively induced both Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Complement-Dependent Cytotoxicity (CDC) in various CLDN6-positive ovarian and testicular cancer cell lines. The potency of these effector functions was notable, with median EC50​ values typically falling within the nanogram per milliliter (ng/mL) range.[27]
• Apoptosis Induction: While some commercial sources suggest direct apoptosis induction [1], primary research from the developers indicated that direct induction of apoptosis was not a significant contributor to the antitumor effect of the naked IMAB027 antibody.[27] Cell death was primarily attributed to ADCC and CDC.
• Chemosensitization: An interesting finding emerged from studies on cancer cell lines exhibiting heterogeneous CLDN6 expression. Pretreatment of these cells with certain chemotherapeutic agents, such as paclitaxel, was found to upregulate the expression of CLDN6 on the cell surface. This increased target antigen density subsequently sensitized the cells to IMAB027-induced ADCC, leading to enhanced cell lysis.[27] This observation provided a strong rationale for exploring combination therapies of IMAB027 with chemotherapy, as the chemotherapy could potentially "unmask" or increase the target for the antibody, thereby improving its efficacy in tumors with variable CLDN6 levels.

B. In Vivo Studies (Xenograft Models)

The in vitro activity of IMAB027 was further investigated in in vivo animal models to assess its anti-tumor efficacy in a more complex biological system.

• Antitumor Efficacy as Monotherapy: When administered as a single agent, IMAB027 demonstrated significant anti-tumor effects in various xenograft mouse models established with human CLDN6-positive cancer cells. These studies showed that IMAB027 could reduce tumor growth and improve overall survival. Such effects were observed in models of both early and advanced ovarian cancer.[1] Similarly, ASP1650 (IMAB027) showed potent antitumor activity in preclinical models of testicular germ cell tumors (GCT).[3]
• Combination Therapy Efficacy: Building on the in vitro chemosensitization findings, the combination of IMAB027 with paclitaxel was tested in vivo. In mice bearing CLDN6-positive xenografts, the combination therapy resulted in a more pronounced prolongation of survival compared to treatment with paclitaxel alone, supporting the potential for synergistic or additive effects.[27]

The promising preclinical in vivo efficacy, observed both as a monotherapy and in combination with chemotherapy, provided a solid foundation for advancing IMAB027 into human clinical trials. However, it is important to note a common challenge in oncology drug development: robust anti-tumor effects in preclinical xenograft models do not always translate directly into equivalent levels of efficacy in human patients. The subsequent clinical trial results for IMAB027 monotherapy, particularly in refractory germ cell tumors (detailed in Section V), indicated that the efficacy observed preclinically was not fully recapitulated in that specific human setting. This discrepancy can be attributed to numerous factors, including differences in the tumor microenvironment, the complexity of the human immune system versus that in immunodeficient mouse models, and pharmacokinetic and pharmacodynamic variations between species.

Table III: Summary of Key Preclinical Findings for IMAB027 (Naked Antibody)

Study Type	Model/System	Key Finding(s)	Source(s)
In Vitro Binding	CLDN6-expressing cell lines, CLDN6 Protein-VLP	Specific binding to CLDN6; no cross-reactivity with CLDN3, 4, 9. EC50​ for binding to CLDN6-VLP: 2.295 ng/mL.	1
In Vitro Cytotoxicity	CLDN6+ ovarian and testicular cancer cell lines	Induction of target-selective ADCC and CDC; median EC50​ values in ng/mL range.	27
In Vitro Apoptosis	CLDN6+ cancer cell lines	Direct induction of apoptosis not a major contributor to antitumor effect for the naked antibody.	27
In Vitro Chemosensitization	CLDN6+ cancer cell lines with heterogeneous expression	Pretreatment with chemotherapy (e.g., paclitaxel) upregulated CLDN6 expression and sensitized cells to IMAB027-induced ADCC, increasing cell lysis.	27
In Vivo Efficacy (Ovarian Cancer)	Mouse xenograft models with human CLDN6+ ovarian cancer cells (early/advanced)	Reduced tumor growth and increased overall survival as a single agent.	1
In Vivo Efficacy (Testicular Cancer)	Preclinical models of testicular GCT	Demonstrated significant antitumor effects as a single agent (ASP1650).	3
In Vivo Combination Therapy	Mice with CLDN6+ xenografts	IMAB027 in combination with paclitaxel prolonged survival compared to paclitaxel alone.	27

V. Clinical Development and Findings for IMAB027 (Naked Antibody)

The promising preclinical profile of IMAB027 led to its evaluation in human clinical trials, primarily focusing on ovarian cancer and germ cell tumors, malignancies known to frequently express CLDN6.

A. Phase I/II OVAR Trial (NCT02054351) in Advanced Ovarian Cancer

The first-in-human clinical trial of IMAB027 was an open-label, dose-escalation Phase I/II study, designated OVAR (NCT02054351), initiated by Ganymed Pharmaceuticals around February 2014.[24] This trial aimed to assess the safety, tolerability, pharmacokinetics (PK), and preliminary clinical efficacy (using RECIST 1.1 criteria) of IMAB027 as a single agent in patients with recurrent, advanced ovarian cancer whose tumors expressed CLDN6.[25] Patient selection based on CLDN6 expression in tumor biopsies was a key feature of the trial design, underscoring the targeted nature of the therapy.[26] The trial was conducted in Germany, Belgium, Russia, and Ukraine.[26]

Preliminary data from the Phase I portion of the OVAR trial, based on 12 patients enrolled as of August 15, 2014, were reported.[25] Patients received IMAB027 intravenously every three weeks (q3w) at escalating dose levels of 100, 300, 600, or 1000 mg/m² (n=3 per group). The enrolled patients typically had a median age of 64 years, presented with platinum-resistant disease, and had undergone a median of four prior lines of chemotherapy, indicating a heavily pre-treated population.

• Safety and Tolerability (Phase I): All administered doses of IMAB027 were reported to be safe and well-tolerated. No dose-limiting toxicities (DLTs) were observed, and the maximum tolerated dose (MTD) was not reached within the tested range. The majority of adverse events (AEs) were mild to moderate (Grade 1-2). Out of 108 AEs recorded, 29 were considered related to IMAB027 by the investigators (22 Grade 1, 6 Grade 2, 1 Grade 3). There was one drug-related serious adverse event (SAE), a Grade 2 hypersensitivity reaction, which was manageable and fully resolved.[25]
• Pharmacokinetics (Phase I): The pharmacokinetic profile of IMAB027 was reported to be well-described by a two-compartment model, with mean AUC ranging from 20,770 to 86,160 µg/mL×h and mean Cmax​ from 151 to 611 µg/mL for the 300 to 1000 mg/m² doses.[25]
• Efficacy (Phase I, Preliminary): The report mentioned that "first signs of IMAB027 clinical activity were observed" [25], although specific details on response rates were not provided in that preliminary abstract.

The initial conclusion from these Phase I data was that IMAB027 appeared to be a safe and well-tolerated treatment option for women with recurrent, advanced ovarian cancer, warranting further clinical evaluation in this patient population with high unmet medical need.[25] The trial was initially anticipated to be completed in 2016.[24] The early safety profile and hints of clinical activity in ovarian cancer provided initial support for the CLDN6-targeting concept.

B. Phase II Trial (NCT03760081 / 1650-CL-0201) in Platinum-Refractory Germ Cell Tumors (GCT)

Following the acquisition by Astellas, IMAB027 (now also referred to as ASP1650) was further evaluated in a Phase II clinical trial (NCT03760081; Astellas ID: 1650-CL-0201) specifically targeting male patients with incurable, platinum-refractory germ cell tumors.[3] This open-label, single-arm, multicenter study included an initial safety run-in phase followed by a Simon's two-stage design for the Phase II portion.

• Safety Run-in and Recommended Phase II Dose (RP2D): The safety run-in part evaluated ASP1650 at dose levels of 1000 mg/m² and 1500 mg/m². No DLTs were observed during this phase. Based on the assessment by a Dose Evaluation Committee, the RP2D of ASP1650 was established at 1500 mg/m² administered intravenously every two weeks.[3]
• Patient Population: A total of 19 male patients were enrolled between March 2019 and October 2020. The median age was 37.2 years (range 20-58). The majority of patients (17/19) had non-seminoma GCT. This was a heavily pre-treated cohort, with a median of three prior chemotherapy regimens, and 13 of the 19 patients had previously received high-dose chemotherapy.[3] CLDN6 expression was centrally assessed on archival tumor tissue; of the 16 subjects with available tissue, 15 (93.8%) had CLDN6 positive staining, with a mean percent membrane staining of 71.6%.[3]
• Efficacy Results: Despite the high target expression and established RP2D, ASP1650 monotherapy demonstrated a lack of clinically meaningful anti-tumor activity in this patient population:
• Overall Response Rate (ORR): No patients achieved a partial or complete response. The ORR, as assessed by modified RECIST v1.1 criteria (which included serum tumor markers βhCG and AFP), was 0% (95% CI, 0.0–14.6%).[3]
• Stable Disease (SD): Three patients (one in the 1000 mg/m² safety lead-in group and two in the 1500 mg/m² group) achieved stable disease as their best response. One patient in the 1500 mg/m² cohort maintained stable disease for over 3 months (166 days).[3]
• Clinical Benefit Rate (CBR): The CBR (defined as CR + PR + SD ≥ specified duration) was 5.3% (95% CI, 0.3–22.6%).[3]
• Tumor Markers: None of the patients on study exhibited a confirmed and continued decline in serum tumor markers (AFP and βhCG) while on treatment.[3]
• Progression-Free Survival (PFS): The median PFS at the RP2D was 1.18 months (95% CI, 0.92–1.48).[3] At the most recent follow-up reported, all patients had experienced disease progression, and eight patients had died due to disease progression.[3]
• Safety and Tolerability: ASP1650 was generally well-tolerated in this study. The most frequently reported treatment-emergent adverse events (TEAEs, regardless of attribution) included anemia (31.6%, all Grade ≥3), abdominal pain (15.8%, 10.5% Grade ≥3), nausea (15.8%, 5.2% Grade ≥3), vomiting (15.8%, 5.2% Grade ≥3), and decreased appetite (15.8%, 5.2% Grade ≥3). Seven patients (36.8%) experienced a drug-related TEAE, and one patient (5.3%) had a drug-related serious TEAE. Importantly, there were no drug-related AEs that led to treatment discontinuation or death.[3]
• Study Termination and Conclusion: Due to the lack of efficacy, the trial was terminated at the completion of Simon Stage I. The protocol stipulated that at least two objective responses were required in the RP2D cohort to proceed to the second stage, a criterion that was not met.[3] The study concluded that ASP1650, as a single agent, did not demonstrate clinically meaningful activity in male patients with relapsed/refractory GCT, despite the high prevalence of CLDN6 expression in their tumors.[3]

The failure of IMAB027/ASP1650 monotherapy in this challenging GCT population, despite adequate target expression and a favorable safety profile, underscores the difficulties often encountered when relying solely on immune-mediated mechanisms like ADCC and CDC for substantial tumor regression in heavily pre-treated and aggressive cancers. Factors such as an immunosuppressive tumor microenvironment, insufficient recruitment or activation of effector immune cells, or a high tumor burden might have contributed to the limited efficacy. This outcome likely reinforced the rationale for developing more potent CLDN6-targeting strategies, such as ADCs, which can deliver a direct cytotoxic payload to the tumor cells.

C. Current Status in Astellas Pipeline

Astellas Pharma's publicly available R&D pipeline updates, as of April 2025 (covering FY2024), do not explicitly list IMAB027 or ASP1650 as an ongoing development program for monotherapy.[15] The company's oncology focus appears to be directed towards other assets, including zolbetuximab (targeting CLDN18.2) and other novel modalities. The absence of IMAB027/ASP1650 monotherapy from these recent pipeline disclosures, in conjunction with the GCT trial results, strongly suggests that its development as a standalone naked antibody has been discontinued or significantly deprioritized by Astellas. However, the intellectual property associated with the antibody and the validation of CLDN6 as a target may still hold value for other therapeutic applications, potentially including ADCs developed by Astellas or other entities.

Table IV: Summary of IMAB027 (Naked Antibody) Clinical Trials

Trial ID (NCT No.)	Phase	Indication	Key Objectives	No. of Patients (Reported)	IMAB027 Dosing	Key Safety Findings	Key Efficacy Findings (Preliminary/Final)	Status/Conclusion	Source(s)
NCT02054351 (OVAR)	I/II	Recurrent, Advanced CLDN6+ Ovarian Cancer	Assess safety, tolerability, PK, and preliminary efficacy of IMAB027.	12 (Phase I, Aug 2014 data)	100, 300, 600, 1000 mg/m² q3w IV	All doses well tolerated, MTD not reached. Most AEs Gr 1-2. One drug-related Gr 2 hypersensitivity SAE (resolved).	"First signs of IMAB027 clinical activity were observed."	Phase I data supported further evaluation. Trial completion expected 2016.	24
NCT03760081 (1650-CL-0201)	II	Incurable Platinum Refractory Germ Cell Tumors	Establish RP2D (safety run-in); Evaluate antitumor activity (Phase II).	19 (Safety run-in & Phase II Stage I)	Safety run-in: 1000, 1500 mg/m²; RP2D: 1500 mg/m² q2w IV	Generally well-tolerated. No DLTs. Most frequent TEAEs: anemia, abdominal pain, nausea. One drug-related SAE. No treatment discontinuations or deaths due to drug-related AEs.	ORR: 0%. SD: 3 patients (16%). CBR: 5.3%. Median PFS at RP2D: 1.18 months. No confirmed tumor marker decline.	Terminated at Stage I due to lack of efficacy. ASP1650 did not show clinically meaningful single-agent activity. CLDN6 remains a valid target. Study completed Oct 2020.	3

VI. IMAB027 in Antibody-Drug Conjugate (ADC) Development: IMAB027-vcMMAE

The development of IMAB027 extended beyond its evaluation as a naked antibody into the realm of antibody-drug conjugates (ADCs). This strategic shift aimed to leverage the antibody's tumor-targeting specificity to deliver a potent cytotoxic payload directly to CLDN6-expressing cancer cells, a common approach to enhance therapeutic efficacy.

A. Rationale for ADC Development

The primary rationale for developing an ADC based on an anti-CLDN6 antibody like IMAB027 was to significantly augment its anti-tumor potency. While naked antibodies rely on immune effector mechanisms (ADCC, CDC) or direct signaling disruption, ADCs add a direct cell-killing mechanism by delivering a highly cytotoxic drug. This can be particularly advantageous for:

1. Overcoming the limitations observed with naked antibody monotherapy, especially in refractory or aggressive cancers where immune-mediated killing might be insufficient [Insight 5.2].
2. Achieving more profound and durable tumor regression by combining the specificity of the antibody with the power of a cytotoxic agent.
3. Potentially reducing the systemic toxicity of the payload compared to traditional chemotherapy by ensuring its targeted delivery to cancer cells, thereby widening the therapeutic window.[14] The development of IMAB027-vcMMAE thus represented a logical progression to harness the tumor-specific binding of an anti-CLDN6 antibody for a more potent therapeutic effect.

B. Composition of IMAB027-vcMMAE (Potentially CLDN6-23-ADC)

The ADC construct, often referred to as IMAB027-vcMMAE or potentially related to CLDN6-23-ADC, comprised three key components:

• Antibody: An anti-CLDN6 monoclonal antibody. While the original IMAB027 was chimeric, sources discussing this ADC often refer to the antibody component as "humanized".[7] This suggests that a humanized version of the anti-CLDN6 antibody was likely used for the ADC to minimize immunogenicity and optimize its pharmacokinetic properties as a delivery vehicle.
• Linker: A lysosomally cleavable dipeptide linker, specifically valine-citrulline (vc).[8] This type of linker is designed to be stable in systemic circulation, preventing premature release of the payload. Upon internalization of the ADC into the target tumor cell and trafficking to lysosomes, the linker is cleaved by lysosomal proteases (like Cathepsin B), releasing the active cytotoxic drug.
• Payload: Monomethyl auristatin E (MMAE), also known as vedotin. MMAE is a potent synthetic antineoplastic agent that functions as a microtubule inhibitor, disrupting microtubule dynamics, leading to cell cycle arrest at the G2/M phase and subsequent apoptosis.[7]

The selection of these components—a humanized IgG1 antibody, a valine-citrulline linker, and an MMAE payload—reflects the use of well-established and clinically validated ADC technologies. This approach leverages proven chemistry for linker stability and payload efficacy, allowing the innovation to focus on the novel CLDN6 target and the specificity of the antibody.

C. Preclinical Characterization of IMAB027-vcMMAE

Extensive preclinical studies were conducted to evaluate the activity and safety of IMAB027-vcMMAE:

• Binding and Internalization: IMAB027-vcMMAE demonstrated robust binding to CLDN6-expressing cells and was efficiently internalized by these cells, a prerequisite for payload delivery to the intracellular environment.[28]
• In Vitro Cytotoxicity: The ADC exhibited potent cytotoxic effects against CLDN6-positive ovarian cancer (OC) and testicular cancer (TC) cell lines, reducing cell viability by up to 100% with EC50​ values in the low nanomolar or ng/mL range. This cytotoxic effect was dose-dependent and led to the induction of apoptosis in the target cells.[28]
• Retained Effector Functions: Importantly, the conjugation process did not abrogate the inherent immune effector functions of the antibody component. IMAB027-vcMMAE retained the ability to induce ADCC and CDC against CLDN6-positive cells, adding another layer to its anti-tumor activity beyond payload delivery.[28]
• Bystander Effect: A significant finding was the observation of a "bystander effect." In co-culture experiments involving CLDN6-positive and CLDN6-negative cells, IMAB027-vcMMAE was able to kill not only the CLDN6-positive target cells but also nearby CLDN6-negative cells.[8] This occurs when the released MMAE payload diffuses out of the target cell and enters adjacent tumor cells, regardless of their CLDN6 expression status. The bystander effect is crucial for addressing tumor heterogeneity, where not all cancer cells within a tumor may express the target antigen.
• In Vivo Antitumor Activity: In mouse xenograft models of human ovarian cancer, a single intravenous administration of IMAB027-vcMMAE (e.g., at 16 mg/kg) resulted in significant antitumor effects, including tumor regression. Notably, the ADC showed efficacy even in xenograft tumors with low and/or heterogeneous CLDN6 expression, an effect likely potentiated by the bystander activity.[28]
• Safety: Repeated dosing of IMAB027-vcMMAE was reported to be well-tolerated in mice, with no observations of physical abnormalities, behavioral changes, or alterations in appearance.[28]

These preclinical data highlighted the substantially enhanced potency of IMAB027-vcMMAE compared to the naked antibody. The direct payload-mediated cytotoxicity, induction of apoptosis, and particularly the bystander killing mechanism, offered advantages for tackling challenging aspects of cancer therapy like tumor heterogeneity.

D. Clinical Development Status of IMAB027-vcMMAE

The available research snippets primarily focus on the preclinical characterization of IMAB027-vcMMAE, with key data presented at the American Association for Cancer Research (AACR) Annual Meeting in 2018.[8] At that time, its development status by Ganymed/Astellas was described as "Early development | Preclinical".[8]

However, a review of Astellas' more recent pipeline updates (e.g., as of April 2025) does not explicitly list IMAB027-vcMMAE or a CLDN6-targeted ADC program under active clinical development by Astellas.[15] While the preclinical data for IMAB027-vcMMAE were compelling, its progression into human clinical trials under Astellas' sponsorship is not evident from these recent public disclosures. This could imply that Astellas chose not to advance this specific ADC candidate further, or its development status is not being highlighted in current public communications. It is also possible that the rights to this specific ADC or the underlying antibody for ADC development were out-licensed or reverted. The field of ADCs is highly competitive, and decisions to advance specific candidates depend on a multitude of factors, including comparative efficacy and safety data against other internal or external programs. Meanwhile, other pharmaceutical companies are actively pursuing the clinical development of different CLDN6-targeted ADCs, such as TORL-1-23 by TORL Biotherapeutics (NCT06690775, Phase 2) [21] and ADCT-242 by ADC Therapeutics [22], indicating continued strong interest in CLDN6 as an ADC target.

Table V: Summary of Preclinical Findings for IMAB027-vcMMAE (ADC)

Study Type	Model/System	Key Finding(s)	Source(s)
In Vitro Binding & Internalization	CLDN6+ human ovarian (OC) and testicular cancer (TC) cell lines	Robust binding to CLDN6-expressing cells; efficient internalization.	28
In Vitro Cytotoxicity (Direct)	CLDN6+ OC and TC cell lines	Reduced cell viability by up to 100% with EC50​ values in the ng/mL range due to MMAE payload.	28
In Vitro Apoptosis (ADC)	CLDN6+ cells	Dose-dependent induction of apoptosis.	28
In Vitro ADCC/CDC (ADC)	CLDN6+ cell lines	Retained ability to induce ADCC and CDC, similar to the naked antibody.	28
In Vitro Bystander Effect	Co-cultures of CLDN6+ and CLDN6-negative cells	Exerted bystander killing of CLDN6-negative cells in proximity to CLDN6+ cells.	8
In Vivo Efficacy	Mouse xenograft models (OC); tumors with low/heterogeneous CLDN6 expression	Significant antitumor effects after single IV administration (16 mg/kg). Efficient tumor size reduction even in tumors with low/heterogeneous CLDN6 expression, potentially driven by bystander activity.	28
In Vivo Safety (ADC)	Mice	Repeated dosing was well tolerated with no physical abnormalities or behavioral changes observed.	28

VII. Synthesis and Future Perspectives

A. Summary of IMAB027's Profile and Development Journey

IMAB027 (ASP1650) emerged as an anti-Claudin 6 (CLDN6) monoclonal antibody with initial promise, primarily due to the highly tumor-restricted, oncofetal expression pattern of its target, CLDN6. As a naked antibody, its proposed mechanisms of action centered on leveraging the host immune system through Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Complement-Dependent Cytotoxicity (CDC). Preclinical studies, both in vitro and in vivo, demonstrated its specificity for CLDN6 and its ability to mediate anti-tumor effects, particularly when combined with chemotherapy in models with heterogeneous target expression.

The clinical development journey of IMAB027 as a monotherapy yielded mixed results. Early Phase I data in advanced ovarian cancer suggested good safety and tolerability with preliminary signs of clinical activity.[25] However, a subsequent Phase II trial in heavily pretreated patients with platinum-refractory germ cell tumors showed a lack of meaningful clinical efficacy, despite adequate target expression and a continued favorable safety profile, leading to the trial's early termination.[3]

This trajectory reflects a common narrative in the development of antibody-based cancer therapies. While a highly specific tumor target like CLDN6 provides a strong rationale, the efficacy of a naked antibody relying on immune effector functions can be limited in advanced, refractory solid tumors. The tumor microenvironment in such cases is often immunosuppressive, and the tumor burden may be too substantial for ADCC/CDC alone to achieve significant clinical responses. This likely spurred the exploration of IMAB027 in an antibody-drug conjugate (ADC) format, IMAB027-vcMMAE. The ADC version demonstrated enhanced preclinical potency, including direct cytotoxic effects and bystander killing, addressing some of the potential limitations of the naked antibody approach.[28] However, the clinical advancement of this specific ADC by Astellas is not apparent in recent disclosures.

B. Challenges and Limitations Observed

The development of IMAB027 highlighted several challenges inherent in antibody-based cancer therapy:

1. Limited Monotherapy Efficacy in Refractory Settings: The GCT trial underscored the difficulty of achieving significant clinical responses with naked antibody monotherapy in patients with advanced, heavily pre-treated cancers, even when the target is well-expressed.[3] The complex tumor microenvironment and established resistance mechanisms in such patients often require more potent therapeutic strategies.
2. Tumor Heterogeneity: While CLDN6 is frequently expressed in target cancers, its expression can be heterogeneous within a tumor. This can limit the efficacy of therapies that solely rely on direct engagement with every cancer cell. The development of ADCs with bystander effects, like IMAB027-vcMMAE, is a strategy to mitigate this challenge.[28]
3. Immunogenicity: The original IMAB027 was described as a chimeric antibody.[1] Chimeric antibodies carry a higher risk of inducing an anti-drug antibody (ADA) response in patients compared to humanized or fully human antibodies. Such ADAs can neutralize the therapeutic effect or lead to hypersensitivity reactions. This potential limitation might have driven the development of a humanized version for the ADC construct [7] to improve its clinical utility.
4. Translation from Preclinical Models: The robust anti-tumor effects observed in preclinical xenograft models did not fully translate to clinical efficacy in the GCT trial. This common issue in oncology drug development can be due to differences in host immune systems (immunodeficient mice vs. human patients), the artificial nature of xenograft models, and complexities in pharmacokinetic/pharmacodynamic scaling.

It is important to contextualize the outcomes of the IMAB027 monotherapy trials. The lack of efficacy in refractory GCT does not necessarily invalidate CLDN6 as a therapeutic target. Instead, it provides valuable information about the level of potency required and the types of therapeutic modalities that might be more successful against such aggressive diseases.

C. The Evolving Landscape of CLDN6-Targeted Therapies

Despite the challenges faced by IMAB027 monotherapy, CLDN6 remains a highly attractive and actively pursued target in oncology. The field has seen the emergence of various next-generation CLDN6-targeted agents, demonstrating continued confidence in its therapeutic potential:

• Antibody-Drug Conjugates (ADCs): Several companies are developing CLDN6-targeted ADCs, employing different antibodies, linkers, and cytotoxic payloads. Examples include DS-9606 (Daiichi Sankyo), TORL-1-23 (TORL Biotherapeutics), and ADCT-242 (ADC Therapeutics), all of which have shown promising early clinical or preclinical activity.[20] These ADCs aim to deliver potent cell-killing agents directly to CLDN6-expressing tumors, potentially overcoming the efficacy limitations of naked antibodies.
• CAR T-Cell Therapies: Chimeric Antigen Receptor (CAR) T-cell therapy targeting CLDN6 is another innovative approach. BNT211 (BioNTech) is a notable example, where CLDN6-directed CAR T-cells are being investigated in combination with a CLDN6-encoding mRNA vaccine (CARVac). The vaccine component is designed to amplify the CAR T-cell response in vivo, potentially leading to more durable efficacy.[20] Early clinical data for BNT211 have shown encouraging responses in patients with CLDN6-positive solid tumors.[20]

This multi-modal pursuit of CLDN6—spanning naked antibodies (historically), ADCs, and CAR T-cell therapies—strongly validates the antigen's importance and druggability. The challenges encountered with one modality (e.g., IMAB027 monotherapy) inform the design and development of others, reflecting a dynamic and evolving therapeutic landscape.

D. Potential Future Research Directions for IMAB027 or CLDN6-Targeting Strategies

Learning from the development journey of IMAB027 and the broader field of CLDN6 targeting, several future research directions can be envisaged:

1. Optimized ADCs: Further exploration of ADCs based on anti-CLDN6 antibodies (potentially derived from or inspired by IMAB027) could involve optimizing linker-payload technologies. This might include novel payloads with different mechanisms of action, linkers with improved stability and cleavage profiles, or antibodies with fine-tuned affinity or effector functions.
2. Rational Combination Therapies: Building on the preclinical observation that chemotherapy can sensitize cells to IMAB027-mediated ADCC by upregulating CLDN6 [27], rationally designed combination strategies are crucial. Combining CLDN6-targeted agents (ADCs or CAR T-cells) with chemotherapy, checkpoint inhibitors, or other targeted therapies could yield synergistic anti-tumor effects and overcome resistance mechanisms.
3. Refined Patient Selection and Biomarkers: While CLDN6 expression is the primary selection biomarker, further refinement could enhance therapeutic outcomes. This might involve establishing quantitative CLDN6 expression thresholds, assessing the impact of target heterogeneity, evaluating the tumor microenvironment's immune status, or identifying co-biomarkers that predict response or resistance.
4. Pediatric Oncology Applications: Given CLDN6's oncofetal antigen status, its potential as a therapeutic target in pediatric solid tumors is an important area for investigation. Recent research supports the viability of CLDN6 as a target in pediatric patients, justifying their inclusion in basket trials for anti-CLDN6 therapies.[15]
5. Bispecific and Multispecific Antibodies: Exploring bispecific or multispecific antibodies that concurrently target CLDN6 and another tumor antigen or an immune effector cell receptor could offer novel therapeutic avenues with enhanced specificity or potency.

VIII. Conclusions

IMAB027 (ASP1650) represents an early pioneering effort in targeting Claudin 6, an oncofetal antigen with a highly tumor-restricted expression profile that makes it an attractive candidate for cancer immunotherapy. Developed initially by Ganymed Pharmaceuticals and later by Astellas Pharma, this chimeric (later potentially humanized for ADC development) IgG1 monoclonal antibody was designed to elicit anti-tumor effects primarily through ADCC and CDC.

Preclinical studies demonstrated promising in vitro and in vivo activity, including specificity for CLDN6, induction of immune-mediated cytotoxicity, and tumor growth inhibition in xenograft models, particularly when combined with chemotherapy. However, the clinical development of IMAB027 as a monotherapy yielded mixed outcomes. While early Phase I data in advanced ovarian cancer showed acceptable safety and preliminary signs of activity, a subsequent Phase II trial in heavily pretreated, platinum-refractory germ cell tumors did not demonstrate clinically meaningful efficacy, leading to its discontinuation in that setting. This highlights the significant challenge of treating advanced, refractory cancers with naked antibodies that rely on host immune effector functions, even when the target is appropriately expressed.

The journey of IMAB027 also led to the development of an antibody-drug conjugate, IMAB027-vcMMAE, which showed enhanced preclinical potency, including direct apoptosis induction and a crucial bystander effect, addressing some limitations of the naked antibody. However, the clinical progression of this specific ADC by Astellas is not apparent in recent public disclosures.

Despite the specific outcomes for IMAB027 monotherapy, the research and development efforts surrounding it have contributed significantly to validating CLDN6 as a bona fide therapeutic target in oncology. The field continues to evolve, with multiple next-generation CLDN6-targeted therapies, including novel ADCs and CAR T-cell therapies, currently under active clinical investigation by various entities. These newer modalities aim to harness the favorable expression profile of CLDN6 with more potent and diverse mechanisms of action.

Future success in targeting CLDN6 will likely depend on the continued optimization of these advanced therapeutic platforms, rational combination strategies, and refined patient selection biomarkers to maximize clinical benefit for patients with CLDN6-expressing cancers. The story of IMAB027 serves as an important case study in the iterative nature of drug development, where initial approaches pave the way for more sophisticated and potentially more effective therapies against challenging oncological targets.

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