Catumaxomab: A Comprehensive Dossier on a Pioneering Trifunctional Antibody for Malignant Ascites

Executive Summary

Catumaxomab is a first-in-class, rat-mouse hybrid, trifunctional bispecific antibody that represents a significant milestone in the field of cancer immunotherapy. This report provides an exhaustive analysis of its molecular characteristics, unique mechanism of action, clinical development, and complex commercial lifecycle. The active substance, Catumaxomab, has been marketed under the brand names Removab® and, more recently, Korjuny®.

The antibody’s innovative design enables it to simultaneously bind three distinct cellular targets: the Epithelial Cell Adhesion Molecule (EpCAM) on tumor cells, the CD3 antigen on T-cells, and activating Fc-gamma (Fcγ) receptors on accessory immune cells such as macrophages and natural killer cells. This unique trifunctionality orchestrates a potent, multi-pronged anti-tumor attack within the local microenvironment, leading to highly effective tumor cell destruction through T-cell-mediated lysis, antibody-dependent cell-mediated cytotoxicity (ADCC), and phagocytosis.

Clinically, Catumaxomab has demonstrated profound and statistically significant efficacy in the intraperitoneal treatment of malignant ascites, a debilitating condition with high unmet medical need. In a pivotal Phase II/III clinical trial, Catumaxomab therapy resulted in a four-fold increase in puncture-free survival compared to standard paracentesis alone, establishing a clear clinical benefit in a palliative care setting.

Despite its proven efficacy, Catumaxomab has had a turbulent commercial history. It was first approved by the European Medicines Agency (EMA) in 2009 as Removab® but was withdrawn from the market in 2017 for commercial reasons, primarily related to the insolvency of its manufacturer, rather than issues of safety or efficacy. The asset was subsequently revived by Lindis Biotech GmbH and, based on the strength of its original data package, successfully regained EMA approval in February 2025 under the new brand name Korjuny®. This revival underscores the drug's enduring clinical value and positions it once again as the only approved, cancer-directed therapy for malignant ascites in Europe.

Catumaxomab serves as both a valuable therapeutic option for a vulnerable patient population and a salient case study in the evolution of bispecific antibodies. The challenges associated with its first-generation, non-humanized design—particularly the systemic toxicity that precluded intravenous use—provided critical lessons that have informed the development of modern, safer T-cell engagers. Its journey from approval to withdrawal and back to market offers profound insights into the complex interplay of scientific innovation, clinical validation, and the commercial realities of the biopharmaceutical industry.

Drug Profile and Molecular Characteristics

Identification and Classification

Catumaxomab is a complex biologic agent with a unique classification that reflects its hybrid origin and multi-faceted mechanism of action. The International Nonproprietary Name (INN) for the active substance is catumaxomab.[1] It was first marketed under the brand name

Removab® and has been reintroduced as Korjuny® following its re-approval.[2]

Pharmacologically, it is classified as a biotech drug belonging to the category of antineoplastic and immunomodulating agents.[1] Its Anatomical Therapeutic Chemical (ATC) classification code is L01FX03, which places it among monoclonal antibodies used in oncology.[1] More specifically, it is defined as a bispecific antibody and, with greater precision, as a

trifunctional antibody (trAb), a designation stemming from its proprietary Triomab® development platform.[4] Its core identifiers are consolidated in Table 1 for reference.

Table 1: Key Drug Identifiers and Properties

Attribute	Value	Source(s)
International Nonproprietary Name (INN)	Catumaxomab	1
Brand Names	Removab®, Korjuny®	2
Drug Type	Biotech, Protein Based Therapy	2
Pharmacological Class	Antineoplastic and Immunomodulating Agent	1
ATC Code	L01FX03	1
DrugBank ID	DB06607	1
CAS Number	509077-98-9	1
UNII	M2HPV837HO	2
Origin	Rat-Mouse Hybrid	2
Isotype	Murine IgG2a-kappa / Rat IgG2b-lambda	8

Chemical Structure and Origin

The molecular architecture of Catumaxomab is central to its function and represents a key innovation in antibody engineering. It is a chimeric rat-mouse hybrid monoclonal antibody, structurally composed of two distinct "half" antibodies covalently linked to form a single, intact, IgG-like molecule.[2] The total molecule consists of 1336 amino acids and has a theoretical molecular weight of approximately 150 kDa.[9]

The two halves are derived from different parental monoclonal antibodies [10]:

1. Anti-EpCAM Arm: One half consists of a mouse IgG2a heavy chain and a kappa light chain. This component is derived from the murine monoclonal antibody HO-3 (also designated Ho-3/TP-A-01/TPBs01), which provides the specificity for the human Epithelial Cell Adhesion Molecule (EpCAM).[10]
2. Anti-CD3 Arm: The other half consists of a rat IgG2b heavy chain and a lambda light chain. This component is derived from the rat monoclonal antibody 26/II/6-1.2 (also designated 26/II/6-1.2/TPBs01), which provides the specificity for the human CD3 antigen on T-cells.[10]

The resulting hybrid molecule possesses a unique combined isotype of Murine IgG2a-kappa / Rat IgG2b-lambda.[8] This specific combination was a deliberate and critical engineering choice designed to overcome the significant manufacturing challenges associated with early bispecific antibody production. Standard quadroma technology, which involves fusing two hybridomas of the same species (e.g., mouse-mouse), results in the random assembly of two different heavy chains and two different light chains. This process can theoretically generate ten different antibody configurations, only one of which is the desired functional bispecific product, leading to extremely low yields and a formidable purification challenge.[13]

The rat-mouse hybrid design of Catumaxomab elegantly circumvents this problem through two mechanisms. First, the use of a mouse IgG2a and a rat IgG2b isotype leads to preferential species-restricted pairing of the heavy and light chains, significantly reducing the formation of mismatched, non-functional antibody variants and thereby enriching the yield of the correct bispecific molecule.[13] Second, this specific isotype combination greatly simplifies purification. The mouse IgG2a heavy chain binds strongly to Protein A, a standard resin used in antibody chromatography, whereas the rat IgG2b heavy chain does not.[13] This differential affinity allows for a straightforward chromatographic separation process to isolate the functional bispecific antibody from parental mouse homodimers, making cost-effective, industrial-scale manufacturing feasible.[13]

However, this innovative manufacturing solution came with a significant clinical trade-off. The non-human origin of the antibody makes it inherently immunogenic in patients, predisposing them to the development of human anti-mouse antibodies (HAMA) and human anti-rat antibodies (HARA).[13] This immunogenicity is a foundational aspect of its clinical profile, contributing to its potent immune-activating effects but also limiting its administration route and necessitating careful patient management. This tension between manufacturability and clinical applicability is a central theme of the Catumaxomab story.

Manufacturing and Formulation

Catumaxomab is produced using quadroma technology, also known as the hybrid-hybridoma technique.[17] The process begins with the somatic fusion of two distinct, antibody-producing hybridoma cell lines: the mouse hybridoma expressing the anti-EpCAM antibody and the rat hybridoma expressing the anti-CD3 antibody.[13] The resulting quadroma cell line co-expresses all four immunoglobulin chains (two heavy, two light), which assemble into the final chimeric antibody.[13] Following cell culture and expression, the antibody is harvested and purified using a process that leverages the differential Protein A binding properties of its mouse and rat components.[13]

For its recent reintroduction as Korjuny®, commercial-scale Good Manufacturing Practice (GMP) production is being conducted by the Celonic Group, a Swiss contract development and manufacturing organization (CDMO), at its facility in Heidelberg, Germany, under a long-term agreement with Lindis Biotech.[20]

The final drug product is supplied as a sterile, preservative-free concentrate for solution for infusion.[21] It is a clear and colorless solution formulated in a 0.1 M sodium citrate buffer at pH 5.6, containing 0.02% polysorbate 80 as a stabilizer.[9] It is provided in pre-filled glass syringes and is available in two presentations: 10 µg of catumaxomab in 0.1 ml of solution, and 50 µg in 0.5 ml, both corresponding to a concentration of 0.1 mg/ml.[21] Prior to administration, the concentrate must be diluted in a sodium chloride 9 mg/ml (0.9%) solution for injection.[22]

Mechanism of Action: A Trifunctional Immunotherapeutic Approach

Catumaxomab’s therapeutic effect is derived from a novel and potent mechanism of action that distinguishes it from conventional monoclonal antibodies. As a trifunctional antibody, it is engineered to physically bridge tumor cells with two distinct arms of the immune system—adaptive (T-cells) and innate (accessory cells)—thereby orchestrating a localized and multi-faceted immunological assault on the cancer.

The Tri-Cell Complex: A Bridge Between Tumor and Immune System

The core of Catumaxomab's function is its ability to simultaneously engage three different cell types, mediating the formation of a "tri-cell complex" that serves as the focal point for tumor destruction.[4] This is achieved through its three distinct binding capabilities:

1. Tumor Cell Targeting via EpCAM: The Fab arm derived from the mouse IgG2a antibody specifically binds to the Epithelial Cell Adhesion Molecule (EpCAM, or CD326).[2] EpCAM is a transmembrane glycoprotein that is highly overexpressed on the surface of the vast majority of epithelial-derived carcinomas, including those that commonly cause malignant ascites such as ovarian and gastric cancers.[9] In normal epithelial tissues, EpCAM expression is typically restricted to the basolateral surface and shielded by tight junctions. In contrast, tumor cells often exhibit diffuse overexpression across the entire cell surface, making EpCAM an accessible and relatively tumor-specific target within the peritoneal cavity.[9]
2. T-Cell Engagement via CD3: The Fab arm derived from the rat IgG2b antibody binds to the CD3 antigen, a key component of the T-cell receptor (TCR) complex found on all mature T-lymphocytes.[2] This interaction directly recruits and engages cytotoxic T-cells, the primary effectors of the adaptive immune system responsible for cell killing.
3. Accessory Cell Activation via the Fc-Region: Unlike many modern engineered antibodies that have inert Fc-regions to minimize off-target effects, Catumaxomab possesses a fully functional and intact Fc-region. This region serves as the third functional binding site, selectively engaging activating Fc-gamma receptors (FcγR) of type I (CD64), IIa (CD32a), and III (CD16).[4] These receptors are expressed on a range of innate immune effector cells, including macrophages, natural killer (NK) cells, and dendritic cells (DCs). Critically, the specific combination of mouse IgG2a and rat IgG2b Fc domains results in an antibody that does not bind to the inhibitory FcγRIIb (CD32b) receptor, thereby avoiding a key mechanism that can dampen immune activation and ensuring a robust pro-inflammatory response.[17]

Elicitation of a Coordinated Anti-Tumor Response

By physically tethering tumor cells to both T-cells and accessory cells, Catumaxomab initiates a powerful and synergistic anti-tumor response through multiple, concurrent killing mechanisms.[17]

• T-Cell-Mediated Lysis: The direct EpCAM-CD3 linkage creates an immunological synapse between the T-cell and the tumor cell. This forced proximity bypasses the need for traditional TCR-MHC recognition, leading to potent T-cell activation and the subsequent release of cytotoxic granules containing perforin and granzymes, which induce rapid lytic death of the targeted tumor cell.[4]
• Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC): The binding of the Fc-region to FcγRIII on NK cells triggers their activation. Activated NK cells then release their own cytotoxic payload, mediating ADCC against the Catumaxomab-coated tumor cell.[4]
• Phagocytosis: The engagement of FcγRI and FcγRIIa on phagocytic cells, such as macrophages and dendritic cells, stimulates them to engulf and destroy the opsonized tumor cells.[4] This process not only eliminates tumor cells but also allows for their antigens to be processed and presented by these professional antigen-presenting cells (APCs), which can prime a broader and more durable adaptive anti-tumor immune response, potentially creating a patient-specific "vaccination effect".[6]

Immunomodulatory Effects and Cytokine Release

The formation and activation of the tri-cell complex is a highly inflammatory event that results in the localized release of a powerful cascade of pro-inflammatory cytokines, which are central to both the drug's efficacy and its side effect profile.[2] This response is characterized by the secretion of key T-helper 1 (TH1) cytokines, including

Interferon-gamma (IFN-γ) and Tumor Necrosis Factor-alpha (TNF-α), along with various interleukins (e.g., IL-2, IL-6).[4]

This intense cytokine milieu further amplifies the anti-tumor response. Moreover, studies have shown that Catumaxomab promotes a form of tumor cell death associated with the hallmarks of immunogenic cell death (ICD), such as the release of ATP and the surface exposure of calreticulin.[27] This "danger signal" makes the dying tumor cells more visible to the immune system, further enhancing the subsequent adaptive immune response.

An important characteristic of this mechanism is that it functions as a "self-supporting system"; the antibody itself provides all the necessary signals to recruit and activate the required immune cells, eliminating the need for any additional co-stimulation or external immune activation.[4]

This potent mechanism directly explains the entirety of Catumaxomab's clinical profile. The powerful, localized immune activation is responsible for the impressive tumor cell killing and clinical benefit observed in trials. Simultaneously, the unavoidable release of systemic cytokines is the direct cause of the most common adverse events, such as fever, chills, and nausea, collectively known as cytokine-release-related symptoms (CRRS).[2] In fact, some clinical analyses have suggested a correlation, though not statistically significant, between the occurrence of CRRS and improved efficacy, indicating that the therapeutic effect and the on-target toxicity are inextricably linked.[28]

From a historical perspective, Catumaxomab's design represents a "brute force" approach to T-cell engagement. Its reliance on an active Fc-region to engage accessory cells, while contributing to its multimodal potency, was also a primary driver of the systemic inflammatory toxicity that proved unmanageable with intravenous administration.[16] The severe liver toxicity observed in IV trials was directly attributed to off-target, Fc-mediated activation of Kupffer cells (liver-resident macrophages) and T-cells.[16] This experience provided a crucial lesson for the field; subsequent generations of T-cell engaging bispecific antibodies have often been engineered with inert or "silent" Fc-regions to mitigate such systemic toxicities, thereby improving safety and allowing for intravenous administration.[16] Thus, Catumaxomab stands as a critical evolutionary data point in the design of bispecific immunotherapies.

Clinical Development and Efficacy in Malignant Ascites

The clinical development program for Catumaxomab was strategically designed to leverage its unique mechanism of action while mitigating the risks associated with its potent immune-activating properties. This led to its focused application in the intraperitoneal treatment of malignant ascites, an indication where it has demonstrated compelling efficacy.

Rationale for Intraperitoneal Administration in Malignant Ascites

Malignant ascites (MA) is the pathological accumulation of fluid in the peritoneal cavity, a frequent and debilitating complication of advanced-stage cancers, particularly those of ovarian, gastric, and colorectal origin.[9] It is associated with a poor prognosis and significantly impairs quality of life, causing symptoms such as abdominal pain, swelling, dyspnea, and malnutrition.[4] Treatment options are limited and primarily palliative, with repeated therapeutic paracentesis (fluid drainage) being the standard of care.[9] This represents a significant unmet medical need.[26]

The rationale for targeting this condition with intraperitoneally administered Catumaxomab is exceptionally strong and based on four key biological principles [4]:

1. Tumor Origin: The primary drivers of MA are epithelial tumors that have metastasized to the peritoneal cavity.
2. Target Expression: These epithelial tumors almost universally overexpress the EpCAM antigen, providing a consistent target for the antibody.
3. Target Specificity: The lining of the peritoneal cavity (the peritoneum) is of mesothelial origin and does not express EpCAM. This makes EpCAM a highly tumor-specific target within this anatomical compartment, minimizing the risk of on-target, off-tumor toxicity to healthy tissues.[17]
4. Immune Cell Availability: The peritoneal cavity and the ascitic fluid contain the necessary immune effector cells (T-cells, macrophages, NK cells) that Catumaxomab requires to execute its mechanism of action.

This localized, intraperitoneal (i.p.) approach is designed to concentrate the drug at the site of disease, thereby maximizing its anti-tumor effect while minimizing the systemic exposure that was found to be unacceptably toxic with intravenous administration.[4]

Pivotal Phase II/III Trial (IP-REM-AC-01)

The cornerstone of Catumaxomab's approval is a large, prospective, randomized, open-label, multicenter Phase II/III trial (NCT00836654).[34] The study enrolled 258 patients with symptomatic MA secondary to EpCAM-positive epithelial cancers for whom standard chemotherapy was no longer feasible or available. Patients were randomized in a 2:1 ratio to receive either paracentesis plus i.p. Catumaxomab or paracentesis alone (control arm).[24]

The treatment regimen consisted of four i.p. infusions of Catumaxomab administered on days 0, 3, 7, and 10, with escalating doses of 10, 20, 50, and 150 µg, respectively.[24]

The choice of the primary endpoint, Puncture-Free Survival (PuFS), was a strategically astute decision. PuFS is a composite endpoint defined as the time from treatment initiation to the first need for a subsequent therapeutic puncture or death, whichever occurred first. In a palliative setting where the primary goal is symptom control and improvement in quality of life, this endpoint directly captures the most clinically meaningful benefit for the patient—delaying the need for a burdensome and repetitive procedure—while also accounting for overall patient decline.[34]

The trial met its primary endpoint with overwhelming statistical significance. Key efficacy results are summarized in Table 2.

Table 2: Summary of Pivotal Phase II/III Trial (IP-REM-AC-01) Key Efficacy Endpoints

Endpoint	Population	Catumaxomab Arm (Median Days)	Control Arm (Median Days)	Hazard Ratio (HR)	p-value	Source(s)
Puncture-Free Survival (Primary)	All Patients	46	11	0.254	<0.0001	34
	Ovarian Cancer	52	11	-	≤0.0001	36
	Non-Ovarian Cancer	37	14	-	≤0.0001	36
Time to Next Paracentesis	All Patients	77	13	0.169	<0.0001	34
Overall Survival	All Patients	72	68	-	Trend	24
	Gastric Cancer	71	44	-	0.0313	34

The results demonstrated a four-fold increase in median PuFS for patients treated with Catumaxomab, corresponding to a 75% reduction in the risk of needing a puncture or death.[24] The median time to the next required paracentesis was extended by more than two months, a highly significant clinical benefit.[34]

In addition to these primary outcomes, Catumaxomab treatment led to a dramatic reduction, and in many cases complete elimination, of EpCAM-positive tumor cells from the ascitic fluid, including cancer stem-like cells (CD133+/EpCAM+).[4] Patients also reported significant improvements in ascites-related signs and symptoms.[34]

While the study was not powered to detect a difference in overall survival (OS), a positive trend was observed in the intent-to-treat population. Notably, a prospectively planned analysis of the gastric cancer subgroup (n=66) revealed a statistically significant prolongation of median OS in the Catumaxomab arm (71 days vs. 44 days, p=0.0313).[34] This finding suggests a potentially greater therapeutic depth in certain tumor types, a tantalizing signal that was not fully explored before the drug's initial market withdrawal. This represents a key area of "unfinished business" and could guide future clinical investigations, perhaps focusing on peritoneal carcinomatosis from gastric cancer where Catumaxomab might offer more than just palliative relief.

Efficacy Across Patient Subpopulations

To confirm the robustness of the treatment effect, a post-hoc analysis of the pivotal trial was performed to evaluate efficacy across various patient subgroups.[36] The analysis confirmed that the significant clinical benefit in PuFS was maintained across all major subpopulations, with a statistically significant treatment effect (p≤0.0001 for all comparisons) observed regardless of:

• Primary Tumor Type: Including both ovarian cancer (median PuFS 52 vs. 11 days) and non-ovarian cancers (median PuFS 37 vs. 14 days).[36]
• Prognostic Factors: Including the presence or absence of distant metastases, the presence of liver metastases, and patient age.[36]

This consistency demonstrates that Catumaxomab provides a broad and reliable clinical benefit to patients within its indicated population.

Supporting Clinical Studies

The pivotal trial was supported by a series of earlier-phase studies that established the foundation for its approval.

• Phase I/II Dose-Finding Study (STP-REM-01): This study in 23 women with refractory ovarian cancer was crucial for defining the treatment regimen. It established the maximum tolerated dose and identified the escalating dose schedule of 10, 20, 50, and 150 µg as the recommended regimen for further investigation.[23] It also provided the first clear signal of efficacy, with 22 of 23 patients not requiring any further paracentesis during the 37-day study period.[23]
• Phase II Re-challenge Study (SECIMAS, NCT01065246): This trial investigated the feasibility of administering a second cycle of Catumaxomab to patients who had previously responded. The study demonstrated that a re-challenge was safe and tolerable, with no acute allergic reactions, even in patients who had developed high levels of anti-drug antibodies (ADAs). Importantly, efficacy was not impaired, suggesting that the ADAs were non-neutralizing and that repeat treatment is a viable option for select patients.[41]
• Additional Phase II and III trials in various indications, including ovarian cancer and a Phase IIIb safety study (CASIMAS, NCT00822809), have further expanded the body of evidence supporting the safety and efficacy of Catumaxomab.[43]

Safety, Tolerability, and Pharmacokinetics

The safety and pharmacokinetic profiles of Catumaxomab are well-characterized and are direct consequences of its immunological mechanism of action and its localized route of administration. Understanding these properties is essential for its safe and effective clinical use.

Comprehensive Safety Profile

The safety profile of Catumaxomab is dominated by on-target effects related to the potent immune activation it induces. The vast majority of adverse events are predictable, manageable, and reversible.[28] The most common adverse reactions are collectively known as

Cytokine-Release-Related Symptoms (CRRS), which stem from the release of pro-inflammatory cytokines upon engagement of immune cells.[28] A detailed breakdown of adverse events by frequency is provided in Table 3.

Table 3: Comprehensive Profile of Adverse Events Associated with Intraperitoneal Catumaxomab

Frequency Category	System Organ Class	Adverse Events	Source(s)
Very Common (≥1/10)	Gastrointestinal disorders	Abdominal pain, Nausea, Vomiting, Diarrhoea	21
	General disorders and administration site conditions	Pyrexia (fever), Fatigue, Chills	21
Common (≥1/100 to <1/10)	Infections and infestations	Infection
	Blood and lymphatic system disorders	Anaemia, Lymphopenia, Leukocytosis	21
	Immune system disorders	Cytokine release syndrome, Hypersensitivity
	Metabolism and nutrition disorders	Decreased appetite, Dehydration, Hypokalaemia
	Psychiatric disorders	Anxiety, Insomnia
	Nervous system disorders	Headache, Dizziness
	Cardiac disorders	Tachycardia	21
	Vascular disorders	Hypotension, Hypertension, Flushing	21
	Respiratory, thoracic and mediastinal disorders	Dyspnoea, Pleural effusion, Cough	21
	Gastrointestinal disorders	Ileus/sub-ileus, Constipation, Abdominal distension	21
	Hepatobiliary disorders	Cholangitis, Hyperbilirubinaemia	22
	General disorders and administration site conditions	Systemic Inflammatory Response Syndrome (SIRS), Pain, Oedema	22
Uncommon (≥1/1,000 to <1/100)	Gastrointestinal disorders	Gastrointestinal haemorrhage, Intestinal obstruction	21
	Renal and urinary disorders	Acute renal failure

Most of these events were reported as CTCAE Grade 1 or 2 in severity and were transient, typically resolving without sequelae following symptomatic treatment.[2] Grade 3 or 4 events were less frequent but did occur, including pyrexia, vomiting, dyspnoea, and hypotension.[21]

Systemic Inflammatory Response Syndrome (SIRS), a more severe manifestation of systemic inflammation, was observed commonly and requires vigilant monitoring.[21]

It is of paramount importance to distinguish the safety profile of intraperitoneal administration from that of intravenous administration. Early clinical attempts to deliver Catumaxomab intravenously had to be terminated due to severe, dose-limiting hepatotoxicity, which included a case of fatal fulminant acute liver failure.[16] This toxicity was directly linked to systemic, Fc-mediated activation of immune cells, particularly Kupffer cells in the liver.[16] This critical finding definitively established that the intraperitoneal route is essential for the drug's acceptable therapeutic index.

Management of Adverse Events

The predictable nature of Catumaxomab's side effects allows for proactive management strategies to ensure patient safety.

• Pre-medication: To mitigate the intensity of CRRS, prophylactic administration of analgesic, antipyretic, and/or non-steroidal anti-inflammatory drugs is recommended prior to each infusion. In clinical trials, 1,000 mg of intravenous paracetamol was routinely administered.[2]
• Patient Monitoring: Close inpatient monitoring is mandatory. The current EMA label for Korjuny® recommends that patients remain hospitalized for 24 hours for observation after the first dose, and for at least 6 hours after subsequent doses.[21]
• Prerequisites for Treatment: Patients must be in adequate clinical condition prior to receiving therapy. This includes a solid performance status (Karnofsky Index > 60 and Body Mass Index > 17 after ascites drainage) and resolution of any acute infections, hypovolemia, hypotension, or acute renal impairment.[21]
• Ascites Drainage: Appropriate medical management of ascites, including drainage until spontaneous flow stops or symptoms are relieved, is a prerequisite before each Catumaxomab infusion to ensure stable circulatory function and aid in drug distribution.[22]

Pharmacokinetic Profile

The pharmacokinetic profile of Catumaxomab following intraperitoneal administration is the key scientific underpinning of its manageable safety. The data consistently demonstrate a paradigm of high local drug concentration with very low systemic exposure.

• Absorption and Distribution: After i.p. infusion, Catumaxomab is distributed throughout the peritoneal cavity and becomes highly concentrated in the ascitic fluid, its intended site of action.[4] Ascites concentrations increase with each successive dose in the treatment cycle, reaching the ng/mL range, which is considered therapeutically effective.[32] Systemic absorption from the peritoneal cavity is minimal; studies show that less than 1% of the administered dose becomes systemically available in the plasma.[32] The geometric mean peak plasma concentration ( Cmax​) is approximately 0.5 ng/mL, orders of magnitude lower than the concentrations achieved locally.[22] This pharmacokinetic partitioning is the reason why the potent immune activation is largely confined to the tumor microenvironment, preventing the severe systemic toxicity seen with IV administration.

An important factor influencing this profile is target-mediated drug disposition. The systemic bioavailability of Catumaxomab is inversely correlated with the burden of EpCAM-positive tumor cells and immune effector cells within the peritoneal cavity.[6] A higher number of cellular targets acts as a "sink," binding the antibody locally and preventing its absorption into the systemic circulation. This creates a potentially self-regulating safety mechanism, whereby patients with the highest disease burden may sequester more of the drug at the site of action, reducing their relative risk of systemic side effects.

• Metabolism and Excretion: As a large protein therapeutic, Catumaxomab is expected to be cleared from the body primarily through catabolism, where it is broken down into smaller peptides and amino acids by proteolytic enzymes throughout the body. These components are then recycled into the general amino acid pool. Specific metabolic pathways have not been detailed in the available literature.[6] It is unknown if Catumaxomab is excreted in human breast milk.[21] The apparent terminal elimination half-life ( t1/2​) from the plasma is approximately 2.1 to 2.5 days, which is relatively long for a murine-based antibody and may be attributable to its hybrid rat/mouse structure.[22]

Regulatory and Commercial Trajectory: A Case Study in Biopharmaceutical Lifecycle

The history of Catumaxomab is a unique and compelling narrative of pioneering innovation, clinical success, commercial failure, and ultimately, resurrection. Its journey provides a valuable case study on the complex factors beyond clinical efficacy that determine a drug's fate in the market. A timeline of key events is presented in Table 4.

Table 4: Timeline of Key Regulatory and Commercial Milestones for Catumaxomab

Date	Event	Key Company/Entity	Brand Name	Source(s)
Apr 20, 2009	Initial EMA Marketing Authorization	Fresenius Biotech	Removab®	2
May 5, 2009	First Market Launch (Germany)	Fresenius Biotech	Removab®	9
Aug 2011	Approval in Israel	-	Removab®	9
May 2012	Health Canada Approval	-	Removab®	9
2013	Voluntary Withdrawal from US Market	-	Removab®	2
2014	Marketing in the EU Discontinued	Neovii Biotech GmbH	Removab®	2
Jun 2, 2017	Official Withdrawal of EU Marketing Authorization	Neovii Biotech GmbH	Removab®	2
Oct 17, 2024	Positive CHMP Opinion for Re-Approval	Lindis Biotech GmbH	Korjuny®	3
Nov 19, 2024	European Commercialization Licensing Deal Signed	Lindis Biotech / Pharmanovia	Korjuny®	26
Feb 12, 2025	European Commission Grants Re-Approval	Lindis Biotech GmbH	Korjuny®	51

Initial Approval and Market Launch (Removab®)

Catumaxomab was developed through a collaboration between Trion Pharma and Fresenius Biotech, based on the foundational scientific work of Dr. Horst Lindhofer.[2] Following the successful pivotal trial, it received its first marketing authorization from the European Medicines Agency (EMA) on April 20, 2009.[2] Marketed as Removab®, its indication was for the intraperitoneal treatment of malignant ascites in patients with EpCAM-positive carcinomas where standard therapy is not available or no longer feasible.[9]

This approval was a landmark event. Catumaxomab was the world's first approved trifunctional antibody, the first approved T-cell engaging bispecific antibody, and the first drug specifically approved for the treatment of malignant ascites.[4] It represented a major validation of a novel therapeutic concept and offered a new option for a patient population with dire need. Approvals in other jurisdictions, including Canada and Israel, followed.[6]

Market Withdrawal (2013-2017)

Despite its clinical promise and innovative status, Removab®'s time on the market was short-lived. Marketing in the European Union ceased after 2014, and the marketing authorization was officially and voluntarily withdrawn at the request of the holder, Neovii Biotech GmbH, on June 2, 2017.[2] The drug was also withdrawn from the US market in 2013.[2]

The officially stated reason for the withdrawal was consistently cited as "commercial reasons".[2] An analysis of the available information reveals that this was not due to a failure of the drug's efficacy or safety, but rather a collapse of its commercial foundation. The primary driver appears to have been the

insolvency of the manufacturer responsible for producing the drug substance.[6] This critical supply chain failure made it impossible to continue marketing the product. Other contributing factors likely included the narrow niche of its approved indication and the clinical limitations imposed by its immunogenicity and inability to be administered intravenously, which capped its potential market size.[16]

This sequence of events presents a powerful case study in the distinction between clinical value and commercial success. Catumaxomab demonstrated a clear, significant, and meaningful benefit for its target population, yet it failed commercially due to logistical and financial vulnerabilities in its supply chain and corporate structure. This highlights that for a drug to reach patients, robust clinical data is necessary but not sufficient; a stable and viable commercial framework is equally critical.

The Path to Re-Approval (Korjuny®)

The compelling clinical data and persistent unmet need for an effective MA treatment provided a strong rationale for reviving the asset. This effort was championed by Lindis Biotech GmbH, a company led by the drug's original inventor, Dr. Horst Lindhofer.[2]

Lindis Biotech successfully navigated the European regulatory process, submitting a new Marketing Authorization Application to the EMA. On October 17, 2024, the EMA's Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the approval of Catumaxomab under the new brand name Korjuny®.[3] The European Commission granted the final marketing authorization on

February 12, 2025, for the same indication as the original Removab® approval.[37]

The re-approval of a drug that had previously failed commercially is a rare event and signals a maturation in the biopharmaceutical market's and regulators' perspectives. It demonstrates a recognition that "commercial failure" is not synonymous with "clinical failure" and reflects a willingness to re-evaluate valuable assets, particularly for niche indications with high unmet need. This success may establish a new paradigm for "drug rescue and revitalization," creating a potential blueprint for identifying and resurrecting other shelved assets whose failures were logistical rather than scientific.

Current Market Landscape and Partnerships

With its re-approval, Korjuny® re-enters a market where it is once again the only approved drug for the specific, cancer-directed treatment of malignant ascites.[26] The unmet medical need remains as high today as it was at the time of its first approval, with no other targeted therapies having emerged for this condition.[31]

To ensure a successful re-launch, Lindis Biotech has adopted an agile partnership model. In November 2024, it signed an exclusive licensing agreement with Pharmanovia, a global pharmaceutical company specializing in commercializing novel and established medicines, to launch and market Korjuny® across Europe.[26] In parallel,

LintonPharm holds the commercialization rights for the Asia-Pacific region and is actively pursuing registration in China, aiming for market penetration within 1-3 years.[51] This specialized, partnered approach may provide a more sustainable commercial model for a niche-indication product compared to its initial launch.

Concluding Analysis and Future Directions

Synthesis of Findings: A Uniquely Positioned Therapeutic

Catumaxomab is a pioneering immunotherapy whose profile is defined by a series of critical dualities. It is a highly effective agent with a potent, multi-faceted mechanism of action that is also demanding in its clinical application. Its innovative rat-mouse hybrid design was both a brilliant solution to manufacturing hurdles and the source of its clinical limitations regarding immunogenicity and administration route. The analysis confirms that its risk-benefit profile is strongly positive within its narrow, approved indication—the localized, intraperitoneal treatment of malignant ascites—but is unfavorable for broader systemic use. The story of Catumaxomab's journey from approval to failure and back to approval serves as a profound lesson in the complex interplay between scientific innovation, clinical reality, and the commercial and logistical frameworks required to bring a valuable medicine to patients.

Potential for Future Development

With its European re-approval secured, the future development of Catumaxomab is likely to focus on expanding its use into other indications where its principle of localized, targeted immunotherapy can be applied.

The most promising and actively pursued area for indication expansion is in non-muscle-invasive bladder cancer (NMIBC).[31] The rationale for this is compelling and directly analogous to its success in malignant ascites. NMIBC is an epithelial cancer that frequently expresses EpCAM. Treatment would involve intravesical administration (instillation directly into the bladder), which, like intraperitoneal administration, would concentrate the drug at the site of the tumor while minimizing systemic exposure and toxicity. Preclinical data have confirmed that Catumaxomab retains its full binding and cytotoxic activity in a urine milieu, supporting the biological feasibility of this approach.[57]

Other potential applications involving localized administration, such as intrapleural therapy for malignant pleural effusions or treatment of peritoneal carcinomatosis in earlier disease stages, could also be explored, though NMIBC appears to be the primary focus of current development efforts.

Broader Implications for Immunotherapy

As the first T-cell engaging bispecific antibody to gain regulatory approval, Catumaxomab was a vanguard molecule that provided essential in-human proof-of-concept for an entire class of therapeutics that is now a pillar of modern oncology. The challenges encountered with its first-generation design have been profoundly instructive for the field. The severe systemic toxicity observed with intravenous administration, driven by its non-human origin and active Fc-region, directly informed the design of subsequent generations of bispecifics. Modern T-cell engagers now routinely incorporate features such as full humanization to reduce immunogenicity and engineered, "silent" Fc domains to abrogate unwanted Fc-receptor interactions, thereby dramatically improving their safety, tolerability, and suitability for systemic use.[16]

Ultimately, Catumaxomab's enduring lesson is that for highly potent immunotherapies, the method and location of administration can be as critical as the molecular mechanism itself. The success of its localized application underscores a valuable strategic principle for managing the toxicity of powerful immune-activating agents, a principle that remains highly relevant as the field continues to develop even more potent and complex therapeutic modalities.

Works cited

1. CATUMAXOMAB - Inxight Drugs, accessed September 4, 2025, https://drugs.ncats.io/drug/M2HPV837HO
2. Catumaxomab - Wikipedia, accessed September 4, 2025, https://en.wikipedia.org/wiki/Catumaxomab
3. EMA Recommends Granting a Marketing Authorisation for Catumaxomab | ESMO, accessed September 4, 2025, https://www.esmo.org/oncology-news/ema-recommends-granting-a-marketing-authorisation-for-catumaxomab
4. Novel Monoclonal Antibodies for Cancer Treatment: The Trifunctional Antibody Catumaxomab (Removab®) - PMC, accessed September 4, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3119393/
5. catumaxomab | Ligand page - IUPHAR/BPS Guide to PHARMACOLOGY, accessed September 4, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=7385
6. Catumaxomab: Uses, Interactions, Mechanism of Action | DrugBank ..., accessed September 4, 2025, https://go.drugbank.com/drugs/DB06607
7. CATUMAXOMAB - precisionFDA, accessed September 4, 2025, https://precision.fda.gov/ginas/app/ui/substances/M2HPV837HO
8. Research Grade Catumaxomab | Cell Sciences, accessed September 4, 2025, https://www.cellsciences.com/research-grade-catumaxomab-21850
9. Australian public assessment report for Catumaxomab, accessed September 4, 2025, https://www.tga.gov.au/sites/default/files/auspar-catumaxomab-140311.pdf
10. Catumaxomab, accessed September 4, 2025, https://access.portico.org/Portico/show?viewFile=pdf&auId=pjbf78xfv1m
11. CAS 509077-98-9: Catumaxomab - CymitQuimica, accessed September 4, 2025, https://cymitquimica.com/cas/509077-98-9/?items=100
12. 509077-98-9 - CAS Common Chemistry, accessed September 4, 2025, https://commonchemistry.cas.org/detail?cas_rn=509077-98-9
13. Design and Production of Bispecific Antibodies - PMC, accessed September 4, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6783844/
14. Bispecific antibody production - ProteoGenix, accessed September 4, 2025, https://www.proteogenix.science/custom-antibody/therapeutic-antibody-services/antibody-engineering/bispecific-antibody/
15. Structural and functional characterization of the trifunctional antibody catumaxomab, accessed September 4, 2025, https://www.researchgate.net/publication/43343058_Structural_and_functional_characterization_of_the_trifunctional_antibody_catumaxomab
16. Catumaxomab – Knowledge and References - Taylor & Francis, accessed September 4, 2025, https://taylorandfrancis.com/knowledge/Medicine_and_healthcare/Oncology/Catumaxomab/
17. Catumaxomab: Clinical development and future directions - PMC, accessed September 4, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2840231/
18. Bispecific antibody: Structure, Formats, and Therapy | Sino Biological, accessed September 4, 2025, https://www.sinobiological.com/resource/antibody-technical/bispecific-antibody
19. Immunotherapeutic progress and application of bispecific ... - Frontiers, accessed September 4, 2025, https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1020003/full
20. Lindis Biotech selects Celonic Group for commercial manufacturing of catumaxomab, accessed September 4, 2025, https://european-biotechnology.com/latest-news/lindis-biotech-selects-celonic-group-for-commercial-manufacturing-of-catumaxomab/
21. Removab, INN-catumaxomab, accessed September 4, 2025, https://ec.europa.eu/health/documents/community-register/2010/2010031575509/anx_75509_en.pdf
22. Removab, INN-catumaxomab - EMA, accessed September 4, 2025, https://www.ema.europa.eu/en/documents/product-information/removab-epar-product-information_en.pdf
23. Review of catumaxomab in the treatment of malignant ascites - PMC, accessed September 4, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3004584/
24. Novel Monoclonal Antibodies for Cancer Treatment: The Trifunctional Antibody Catumaxomab (Removab®) - Journal of Cancer, accessed September 4, 2025, https://www.jcancer.org/v02p0309.htm
25. go.drugbank.com, accessed September 4, 2025, https://go.drugbank.com/drugs/DB06607#:~:text=Catumaxomab%20brings%20cancer%20cells%2C%20T,destruction%20of%20the%20cancer%20cells.
26. Pharmanovia signs novel biologic in-licensing agreement, accessed September 4, 2025, https://pharmanovia.com/news/pharmanovia-signs-novel-biologic-in-licensing-agreement-with-lindis-biotech-to-commercialise-catumaxomab-for-treatment-of-rare-condition-malignant-ascites/
27. Potent Immunomodulatory Effects of the Trifunctional Antibody Catumaxomab | Cancer Research - AACR Journals, accessed September 4, 2025, https://aacrjournals.org/cancerres/article/73/15/4663/584697/Potent-Immunomodulatory-Effects-of-the
28. Safety of catumaxomab: Cytokine-release-related symptoms as a possible predictive factor for efficacy in a pivotal phase II/III trial in malignant ascites - ResearchGate, accessed September 4, 2025, https://www.researchgate.net/publication/343870656_Safety_of_catumaxomab_Cytokine-release-related_symptoms_as_a_possible_predictive_factor_for_efficacy_in_a_pivotal_phase_IIIII_trial_in_malignant_ascites
29. Safety of catumaxomab: Cytokine-release-related symptoms as a possible predictive factor for efficacy in a pivotal phase II/III trial in malignant ascites | Journal of Clinical Oncology - ASCO Publications, accessed September 4, 2025, https://ascopubs.org/doi/10.1200/jco.2009.27.15_suppl.3036
30. Catumaxomab Clinical development and future directions - ResearchGate, accessed September 4, 2025, https://www.researchgate.net/publication/298852912_Catumaxomab_Clinical_development_and_future_directions
31. Scientific Publications & News - Lindis Biotech, accessed September 4, 2025, https://www.lindisbiotech.com/scientific-publications-news/
32. Pharmacokinetics, immunogenicity and bioactivity of the therapeutic ..., accessed September 4, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2878603/
33. Pharmacokinetics, immunogenicity and bioactivity of the therapeutic antibody catumaxomab intraperitoneally administered to cancer patients | Request PDF - ResearchGate, accessed September 4, 2025, https://www.researchgate.net/publication/44689973_Pharmacokinetics_immunogenicity_and_bioactivity_of_the_therapeutic_antibody_catumaxomab_intraperitoneally_administered_to_cancer_patients
34. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial - PubMed, accessed September 4, 2025, https://pubmed.ncbi.nlm.nih.gov/20473913/
35. The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 16 December 2009 REMOVAB 10 microgram con, accessed September 4, 2025, https://www.has-sante.fr/jcms/c_1014983/fr/removab-ct-6973-version-anglaise
36. Clinical benefit of catumaxomab in malignant ascites in patient subpopulations in a pivotal phase II/III trial - ASCO Publications, accessed September 4, 2025, https://ascopubs.org/doi/10.1200/jco.2009.27.15_suppl.e14000
37. Korjuny | European Medicines Agency (EMA), accessed September 4, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/korjuny
38. Immunomonitoring Results of a Phase II/III Study of Malignant Ascites Patients Treated with the Trifunctional Antibody Catumaxomab (Anti-EpCAM × Anti-CD3) - AACR Journals, accessed September 4, 2025, https://aacrjournals.org/cancerres/article/72/1/24/575557/Immunomonitoring-Results-of-a-Phase-II-III-Study
39. LINDIS Biotech receives Positive CHMP Opinion for KORJUNY® (catumaxomab) in the European Union - FirstWord Pharma, accessed September 4, 2025, https://firstwordpharma.com/story/5905272
40. Effective Relief of Malignant Ascites in Patients with Advanced Ovarian Cancer by a Trifunctional Anti-EpCAM × Anti-CD3 Antibody: A Phase I/II Study - AACR Journals, accessed September 4, 2025, https://aacrjournals.org/clincancerres/article-abstract/13/13/3899/193417
41. Catumaxomab Completed Phase 2 Trials for Malignant Ascites Due to Epithelial Carcinoma Treatment | DrugBank Online, accessed September 4, 2025, https://go.drugbank.com/drugs/DB06607/clinical_trials?conditions=DBCOND0046411&phase=2&purpose=treatment&status=completed
42. Results of a phase II clinical trial to evaluate a re-challenge of intraperitoneal catumaxomab for treatment of malignant ascites (MA) due to epithelial cancer (SECIMAS). - ASCO Publications, accessed September 4, 2025, https://ascopubs.org/doi/10.1200/jco.2013.31.15_suppl.5582
43. Catumaxomab Completed Phase 2 Trials for Ovarian Cancer Treatment | DrugBank Online, accessed September 4, 2025, https://go.drugbank.com/drugs/DB06607/clinical_trials?conditions=DBCOND0028213&phase=2&purpose=treatment&status=completed
44. Catumaxomab Completed Phase 2 Trials for Abdominal wall neoplasm / Ovarian Cancer / Fallopian Tube Neoplasms Treatment - DrugBank, accessed September 4, 2025, https://go.drugbank.com/drugs/DB06607/clinical_trials?conditions=DBCOND0010998%2CDBCOND0001244%2CDBCOND0028213&phase=2&purpose=treatment&status=completed
45. Catumaxomab Completed Phase 3 Trials for Carcinoma / Ascites, Malignant / Neoplasms / Cancer Treatment | DrugBank Online, accessed September 4, 2025, https://go.drugbank.com/drugs/DB06607/clinical_trials?conditions=DBCOND0110262%2CDBCOND0020966%2CDBCOND0022280%2CDBCOND0027948&phase=3&purpose=treatment&status=completed
46. Randomised phase II trial to investigate catumaxomab (anti-EpCAM × anti-CD3) for treatment of peritoneal carcinomatosis in patients with gastric cancer - PMC, accessed September 4, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6070920/
47. Adverse events considered related to catumaxomab occurring in !5% of... | Download Table - ResearchGate, accessed September 4, 2025, https://www.researchgate.net/figure/Adverse-events-considered-related-to-catumaxomab-occurring-in-5-of-patients-N-14-157_tbl2_44603065
48. Mechanism of Action and Pharmacokinetics of Approved Bispecific Antibodies, accessed September 4, 2025, https://www.biomolther.org/journal/view.html?uid=1580&vmd=Full&
49. Removab | European Medicines Agency (EMA), accessed September 4, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/removab
50. Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 14-17 October 2024, accessed September 4, 2025, https://www.ema.europa.eu/en/news/meeting-highlights-committee-medicinal-products-human-use-chmp-14-17-october-2024
51. Catumaxomab Approved by European Commission for Intraperitoneal Treatment of Malignant Ascites induced by EpCAM-positive carcinomas - LintonPharm, accessed September 4, 2025, http://www.lintonpharm.com/page1000121?_l=en&article_id=85
52. Removab – Withdrawal of the marketing authorisation in the European Unio - 1stOncology, accessed September 4, 2025, https://www.1stoncology.com/blog/removab-withdrawal-of-the-marketing-authorisation-in-the-european-unio/
53. LINDIS Biotech Receives Positive CHMP Opinion for KORJUNY(R) (catumaxomab) in the European Union - BioSpace, accessed September 4, 2025, https://www.biospace.com/press-releases/lindis-biotech-receives-positive-chmp-opinion-for-korjunyr-catumaxomab-in-the-european-union
54. Pharmanovia Signs Novel Biologic In-Licensing Agreement With Lindis Biotech to Commercialise Catumaxomab for Treatment of Rare Condition, Malignant Ascites - FirstWord Pharma, accessed September 4, 2025, https://firstwordpharma.com/story/5914042
55. EMA CHMP grants positive opinion of Korjuny for malignant ascites - The Cancer Letter, accessed September 4, 2025, https://cancerletter.com/drugs-and-targets/20241025_8d/
56. Pharmanovia Signs Novel Biologic In-Licensing Agreement With Lindis Biotech to Commercialise Catumaxomab for Treatment of Rare Condition, Malignant Ascites - Business Wire, accessed September 4, 2025, https://www.businesswire.com/news/home/20241119386037/en/Pharmanovia-Signs-Novel-Biologic-In-Licensing-Agreement-With-Lindis-Biotech-to-Commercialise-Catumaxomab-for-Treatment-of-Rare-Condition-Malignant-Ascites
57. First time intravesically administered trifunctional antibody catumaxomab in patients with recurrent non-muscle invasive bladder cancer indicates high tolerability and local immunological activity - PMC, accessed September 4, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8360869/