An In-Depth Review of LIS-1 (DB18388): A Novel Glyco-Humanized Polyclonal Antibody for Immunomodulation

I. Executive Summary

LIS-1 (DrugBank ID: DB18388) represents an innovative advancement in therapeutic antibody development, specifically as a glyco-humanized polyclonal antibody (GH-pAb). Its primary design objective is to engage human T-cells, positioning it principally as an induction agent in solid organ transplantation to prevent acute rejection. Emerging research also indicates its exploration in oncological settings, particularly for T-cell malignancies. The core innovation of LIS-1 lies in its production within genetically engineered swine, which lack key xenoantigens responsible for the immunogenicity commonly associated with traditional animal-derived anti-lymphocyte globulins (ALGs). This "glyco-humanization" aims to confer a significantly improved safety and tolerability profile.

The mechanism of action of LIS-1 involves T-cell depletion through complement-mediated cytotoxicity, phagocyte-mediated cytotoxicity, apoptosis, and antigen masking, notably excluding antibody-dependent cell-mediated cytotoxicity (ADCC). Preclinical studies and initial clinical trial data in kidney transplant recipients (NCT04431219) have demonstrated that LIS-1 is well-tolerated, does not elicit detectable anti-drug antibodies, and achieves effective, yet transient, T-cell depletion with rapid lymphocyte repopulation. These characteristics suggest a potential to mitigate the risks of prolonged immunosuppression and high immunogenicity associated with conventional ALGs. The development of LIS-1 by Xenothera SAS, and its associated GH-pAb platform technology, may address substantial unmet medical needs in immunosuppressive therapy and potentially offer new avenues for treating certain cancers.

II. Introduction to LIS-1 (DB18388)

Background and Rationale for Development

LIS-1, identified by DrugBank Accession Number DB18388, is an immunoglobulin G (IgG) polyclonal antibody specifically engineered to bind to human T-cells.[1] The impetus for its development stems from the inherent limitations of existing anti-thymocyte globulins (ATGs) and anti-lymphocyte globulins (ALGs). These conventional therapies, typically derived from animal sources like rabbits or horses, contain carbohydrate xenoantigens, such as α-1,3-galactose ($\alpha$Gal) and N-glycolylneuraminic acid (Neu5Gc), which are highly immunogenic in humans.[2] The human immune system recognizes these xenoantigens as foreign, often leading to the generation of anti-drug antibodies. This immune response can precipitate a range of adverse events, from subclinical inflammatory processes that may compromise long-term graft survival to more overt complications like serum sickness.[2] Furthermore, the potent and often prolonged lymphodepletion caused by traditional ATGs/ALGs elevates the risk of opportunistic infections, a significant concern in immunosuppressed patients.[5]

LIS-1 was conceived to circumvent these challenges. By utilizing a glyco-humanization strategy—producing the antibodies in swine genetically engineered to lack the major immunogenic xenoantigens—the goal is to create a therapeutic agent with reduced immunogenicity and an improved safety profile.[4] This approach aims to provide effective immunosuppression with a more controlled and potentially shorter duration of T-cell depletion, thereby offering a more favorable risk-benefit balance compared to older polyclonal antibody preparations.[6] The transition from merely purifying animal-derived antibodies to proactively re-engineering the biological source (the swine) to be more compatible with the human immune system marks a sophisticated evolution in therapeutic antibody development. This targeted bioengineering directly addresses the fundamental cause of the immunogenicity seen with earlier ALGs. The potential success of such a strategy with LIS-1 could, in turn, validate the broader applicability of Xenothera's glyco-humanized polyclonal antibody (GH-pAb) platform technology.[9] This could stimulate renewed interest in polyclonal antibodies for various therapeutic indications where monoclonal antibodies might have limitations, such as the need to target multiple epitopes for a broader or more robust biological effect.[11]

General Characteristics and Classification

LIS-1 is categorized as a biotechnology-derived therapeutic and is currently in an experimental phase of development.[1] Within the broader classification of protein-based therapies, it is specifically defined as a polyclonal antibody (pAb).[1] It is frequently referred to in literature as a glyco-humanized anti-lymphocyte globulin (GH-ALG), highlighting its modified nature and source.[2]

III. Identification and Physicochemical Properties

Nomenclature and DrugBank Identifier

The generic name assigned to this investigational drug is LIS-1.[1] It is also referred to by the synonyms LIS 1 and LIS1.[1] It is critically important to distinguish this therapeutic antibody, LIS-1 (DB18388), from the endogenous human protein also known as LIS1 (encoded by the PAFAH1B1 gene). The PAFAH1B1 protein plays a vital role in neuronal migration, microtubule organization, and interacts with cytoplasmic dynein; mutations in its gene are associated with lissencephaly.[12] The research snippets [12], and [29] pertain to this intracellular protein and its functions, which are distinct from the therapeutic actions of the LIS-1 antibody. This report is exclusively focused on the LIS-1 polyclonal antibody (DB18388). The DrugBank Accession Number for this therapeutic antibody is DB18388.[1]

Chemical Taxonomy and Known Structural Information

According to the ClassyFire chemical ontology, as provided by DrugBank, LIS-1 is classified within the Kingdom of Organic Compounds, Super Class of Organic Acids, Class of Carboxylic Acids and Derivatives, Sub Class of Amino Acids, Peptides, and Analogues, with Peptides listed as its Direct Parent.[1] This hierarchical classification is typical for proteinaceous entities like antibodies. However, specific details such as the precise protein chemical formula, average molecular weight of the protein mixture, and amino acid sequences are currently listed as "Not Available" in the DrugBank entry for LIS-1.[1] This lack of publicly available, detailed structural information is characteristic of proprietary biologic drugs during their development phase. For complex biologics like polyclonal antibodies, which are inherently mixtures of different antibody molecules, characterization often relies more heavily on functional assays (e.g., binding to target cells, eliciting specific biological effects) and consistency in manufacturing processes, rather than on a singular, defined chemical structure applicable to small-molecule drugs.

Developer

LIS-1 is being developed by Xenothera SAS, a biotechnology company.[6]

Table 1: LIS-1 (DB18388) – Key Identification and Properties

Feature	Details	Reference(s)
Generic Name	LIS-1	1
DrugBank ID	DB18388	1
Background Summary	Immunoglobulin G (IgG) polyclonal antibody; binds to human T-cells; glyco-humanized ALG	1
Drug Type	Biotech, Experimental	1
Biologic Classification	Protein Based Therapies, Polyclonal antibody (pAb)	1
Chemical Taxonomy	Direct Parent: Peptides	1
Developer	Xenothera SAS	6

This table provides a consolidated overview of the fundamental identifying characteristics of LIS-1, serving as a quick reference. The careful distinction between LIS-1 the drug and LIS1 the protein (PAFAH1B1) is essential to avoid confusion, as the shared nomenclature could misdirect literature searches if not explicitly managed. The therapeutic LIS-1 antibody's mechanism is centered on T-cell interaction, not intracellular microtubule dynamics.

IV. Mechanism of Action and Pharmacodynamics

Molecular Target(s) and Binding Characteristics

LIS-1 is an IgG polyclonal antibody preparation that exerts its effects by binding to human T-lymphocytes.[1] As a polyclonal antibody, it comprises a diverse repertoire of antibody molecules, each potentially recognizing different epitopes on the surface of T-cells.[10] This multi-epitope binding capability is a hallmark of polyclonal therapies and can contribute to a robust and multifaceted interaction with the target cell population.

Immunomodulatory Effects (as GH-ALG)

The immunomodulatory activity of LIS1, in its form as a glyco-humanized ALG (GH-ALG), is characterized by several key mechanisms leading to T-cell depletion and functional inhibition. Unlike some other anti-lymphocyte globulins, LIS1's actions are reported to be restricted to complement-dependent cytotoxicity (CDC), phagocyte-mediated cytotoxicity (which likely includes antibody-dependent cellular phagocytosis, ADCP), induction of apoptosis, and antigen masking.[2] A crucial distinction is the exclusion of antibody-dependent cell-mediated cytotoxicity (ADCC) from its effector functions.[2] This specific exclusion of ADCC might be an intentional design element, possibly achieved through Fc region engineering (referred to as "Fc-silenced in humans" [7]), to refine the immunosuppressive impact and potentially reduce inflammatory side effects often associated with robust ADCC engagement, while still achieving effective T-cell modulation.

Experimental evidence supports these mechanisms:

• Apoptosis Induction: LIS1 (GH-ALG) has been shown to induce apoptosis in human lymphocytes in a dose-dependent manner. Significant levels of apoptosis were observed at concentrations as low as 10 µg/ml, with the effect increasing up to a concentration of 300 µg/ml.[2]
• Phagocytosis: Opsonization of T-lymphocytes with LIS1 (GH-ALG) led to significant uptake by monocyte-derived macrophages, indicating effective ADCP.[2]

Collectively, these mechanisms culminate in a profound inhibition of T-cell alloreactivity, as demonstrated in mixed leukocyte reaction assays.[4] This inhibition of alloreactive T-cells is central to its therapeutic rationale in preventing transplant rejection.

Comparison with Conventional Anti-Lymphocyte/Anti-Thymocyte Globulins (ALGs/ATGs)

LIS-1 was developed to overcome significant drawbacks of conventional ALGs/ATGs:

• Immunogenicity: Traditional ALGs/ATGs are associated with high immunogenicity due to the presence of carbohydrate xenoantigens (Neu5Gc and $\alpha$Gal). This can lead to the formation of anti-drug antibodies, hypersensitivity reactions like serum sickness, and potentially diminish the long-term efficacy or survival of transplanted grafts.[2] LIS-1, being produced in DKO swine lacking these xenoantigens, is designed to be substantially less immunogenic.[4]
• Lymphodepletion Profile: Conventional ALGs/ATGs often cause profound and prolonged lymphodepletion, which, while contributing to immunosuppression, also increases the recipient's susceptibility to opportunistic infections.[2] LIS-1 is suggested to induce a more transient T-cell depletion, with a comparatively faster recovery of lymphocyte populations.[3] This "hit hard and recover fast" profile could be optimal for induction, providing strong initial protection against acute rejection when the alloimmune response is most intense, followed by a quicker restoration of immune competence to combat infections. This might, in turn, reduce the overall duration or intensity of subsequent maintenance immunosuppression.

Pharmacodynamic Profile from Preclinical and Clinical Studies

• Preclinical Evaluation (Non-Human Primates): Studies in macaques revealed that LIS1 (GH-ALG) selectively impacted CD4+ and CD8+ effector T-cells, while notably sparing T-regulatory cells (T-regs), B-cells, and myeloid cells.[5] It induced a transient depletion of target T-cells in peripheral blood (to <100 lymphocytes/µL) lasting less than one week. Despite this shorter depletion phase compared to rabbit ATG, LIS1 demonstrated equivalent efficacy in preventing allograft rejection in a skin transplant model.[3] The sparing of T-regulatory cells, if translatable to human therapy, could be a significant advantage. T-regs are crucial for maintaining immune homeostasis and promoting tolerance to allografts. An agent that selectively depletes pathogenic effector T-cells while preserving or even promoting T-reg populations could foster a more favorable immunological environment for long-term graft acceptance and potentially reduce the reliance on chronic, broad-spectrum immunosuppressants.
• Clinical Evaluation (Kidney Transplant Recipients, NCT04431219): In the first-in-human study, administration of LIS1 at doses of 6, 8, and 10 mg/kg resulted in depletion of CD3+ T-cells to below 100/mm³ by day 2.[4] Consistent with preclinical findings, lymphocyte repopulation was rapid, with pre-transplant levels of lymphocyte subpopulations recovering within 2 to 4 weeks.[4] This relatively fast lymphocyte recovery, compared to the potentially more extended depletion seen with some traditional ATGs, could directly translate to a narrower window of vulnerability to opportunistic infections, a major concern with intensive immunosuppressive regimens.

Table 4: Comparative Features of LIS-1 (GH-ALG) vs. Traditional ATGs/ALGs

Feature	LIS-1 (GH-ALG)	Traditional ATGs/ALGs (General)	Reference(s) for LIS-1
Source Animal	Genetically modified (DKO) swine	Rabbit, Horse	4
Key Xenoantigens	Lacks $\alpha$Gal and Neu5Gc	Contains $\alpha$Gal and Neu5Gc	4
Immunogenicity Profile	Low; no anti-LIS1 antibodies detected in Phase 1	High; risk of anti-drug antibodies, serum sickness	4
Primary MoA Components	CDC, Phagocytosis (ADCP), Apoptosis, Antigen Masking	CDC, ADCC, Apoptosis, Phagocytosis, other non-destructive mechanisms	2
ADCC Activity	Excluded (Fc-silenced)	Present	2
T-reg Sparing	Observed in preclinical studies (macaques)	Variable; often less selective	5
Duration of T-cell Depletion	Transient (e.g., <1 week in NHP); rapid recovery (2-4 weeks in humans)	Often strong and long-lasting	3
Key Reported Adverse Events	Well-tolerated in Phase 1; no CRS or severe cytopenias specifically noted for LIS1	Fever, chills, skin rashes, serum sickness, anaphylaxis, cytopenias	3

This table underscores the key differentiators of LIS-1, which form the basis of its development rationale and potential clinical advantages.

V. Pharmacokinetics

Absorption, Distribution, Metabolism, and Excretion (ADME)

LIS-1 is administered via intravenous infusion.[5] As an IgG polyclonal antibody, its distribution is expected to primarily involve the plasma and extracellular fluid compartments. The metabolism of LIS-1, like other IgG antibodies, is presumed to occur via general protein catabolism pathways, where it is broken down into smaller peptides and amino acids by proteolytic enzymes throughout the body, particularly within the reticuloendothelial system. Specific, detailed ADME parameters beyond half-life are not extensively provided in the available documentation.

Half-life and Lymphocyte Repopulation Dynamics

The first-in-human clinical trial in kidney transplant recipients (NCT04431219) provided key pharmacokinetic insights. The terminal half-life of LIS1 was determined to be 33.7 days.[4] The drug exhibited linear disposition, which is a favorable characteristic, suggesting that its clearance mechanisms are not saturated within the therapeutic dose range and that exposure levels are generally proportional to the administered dose.[4] This predictability simplifies dosing considerations.

Despite the relatively long terminal half-life, which indicates a prolonged presence of the antibody in circulation, the functional effect on lymphocyte counts was more temporally defined. Lymphocyte repopulation was observed to be notably fast, with pretransplant counts of various lymphocyte subpopulations recovering within 2 to 4 weeks following the completion of LIS1 administration.[4] This apparent disconnect between the physical presence of the drug (suggested by its half-life) and the duration of its profound T-cell depleting effect is significant. It may imply that the concentration of LIS-1 required to maintain maximal T-cell depletion falls below a critical threshold relatively quickly, or that compensatory homeostatic mechanisms for lymphocyte production are rapidly engaged. Understanding this relationship between exposure and dynamic response is crucial for optimizing dosing schedules and predicting the period of heightened infection risk. The question of how these pharmacokinetic parameters, particularly linearity and half-life, translate across diverse patient populations (e.g., individuals with varying degrees of renal impairment, different baseline inflammatory states, or co-morbidities) will be important to address in broader clinical studies.

VI. Clinical Development and Therapeutic Applications

A. Primary Indication: Solid Organ Transplantation (Induction Therapy)

LIS-1 is primarily being developed as an induction immunosuppressive agent for patients undergoing solid organ transplantation.[2] The core objective of induction therapy is to provide robust, early immunosuppression to prevent acute allograft rejection, which is most common in the immediate post-transplant period.[4] LIS-1 aims to achieve this by effectively depleting T-lymphocytes, the key mediators of acute rejection, while offering potential advantages over traditional ATGs, such as reduced immunogenicity and a more controlled T-cell depletion profile with faster recovery.[7]

Clinical Trial NCT04431219

The cornerstone of LIS-1's clinical development in transplantation is the NCT04431219 study, titled "First in Human Study for the Assessment of Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Multiple Ascending Intravenous Doses of LIS1 in Kidney Transplanted Patients".[17]

• Phase and Status: This was a Phase 1, first-in-human, open-label, single-site, dose-escalation study.[4] Some sources also refer to it as a Phase I/II study, likely reflecting its design which included dose-finding and cohort expansion elements.[9] The trial was conducted in the Czech Republic and completed in 2022.[17]
• Developer/Sponsor: While not explicitly stated in all trial-specific snippets, Xenothera SAS is the developer of LIS-1.[6]
• Patient Population: The study enrolled primary kidney transplant recipients. An ascending dose cohort (n=5) comprised patients at low immunological risk (Panel Reactive Antibody < 20%). A subsequent therapeutic dose cohort (n=5) included patients with PRA <50% who did not have donor-specific antibodies.[4]
• Intervention: LIS1 was administered intravenously for 5 consecutive days. The ascending dose cohort received doses of 0.6, 1, 3, 6, or 8 mg/kg. In the therapeutic dose cohort, two patients received 8 mg/kg, and three patients received 10 mg/kg.[4]
• Key Findings:
• Safety and Tolerability: LIS1 demonstrated a favorable safety profile and was well tolerated. Importantly, no instances of cytokine release syndrome (CRS), severe thrombocytopenia, or severe leukopenia were reported.[4] No hypersensitivity or infusion-related reactions necessitating discontinuation occurred, and no serious adverse events were attributed to the study drug.[4]
• Efficacy/Pharmacodynamics (T-cell depletion): Effective T-cell depletion (CD3+ T-cells <100/mm³) was observed by day 2 in all patients who received LIS1 at doses of 6, 8, and 10 mg/kg. As noted previously, lymphocyte repopulation was rapid, with counts returning to pretransplant levels within 2 to 4 weeks.[4]
• Immunogenicity: A critical outcome was the absence of detectable anti-LIS1 antibodies in treated patients.[4] This finding strongly supports the success of the glyco-humanization strategy in mitigating the immunogenic potential of the swine-derived antibodies.
• Pharmacokinetics: The terminal half-life of LIS1 was 33.7 days, and its disposition was linear.[4]
• Study Conclusions: The investigators concluded that this genome-edited, swine-derived polyclonal LIS1 ALG was well tolerated, did not elicit anti-drug antibodies, and induced a time-limited T-cell depletion in low- and medium-risk kidney transplant recipients.[4] The study successfully met its pharmacodynamic and safety endpoints.[17] The successful completion of NCT04431219, particularly the lack of anti-drug antibodies, serves as a significant validation for Xenothera's entire GH-pAb platform. This de-risks not only LIS-1 for transplantation but also enhances the prospects for other GH-pAbs in their pipeline targeting different diseases, such as LIS22/XON7 for oncology and XAV-19 for infectious diseases.[9] It provides compelling evidence that genetic modification of the source animal can effectively "humanize" animal-derived antibodies to evade detection by the human immune system.

Advantages of LIS-1 in Transplantation

The data from NCT04431219 and preclinical studies highlight several potential advantages of LIS-1:

• Reduced Immunogenicity: The primary advantage, stemming from the elimination of $\alpha$Gal and Neu5Gc xenoantigens.[4]
• Favorable Safety Profile: Well-tolerated in early clinical assessment.[4]
• Controlled T-cell Depletion and Recovery: Offers effective initial immunosuppression with a faster return of lymphocyte counts, potentially reducing the window for opportunistic infections.[4]
• Potential T-reg Sparing: Preclinical evidence suggests sparing of T-regulatory cells, which could promote long-term allograft tolerance.[5]

Regulatory Status and Future Development for Transplantation

LIS1 has received Orphan Drug Designation for use in solid organ transplantation from both the U.S. Food and Drug Administration (FDA) in 2020 and the European Medicines Agency (EMA) in 2022.[9] Following the completion of the Phase 1/2 study, Xenothera announced plans for a confirmatory Phase II/III trial, which was anticipated to begin in 2023.[14] The first-in-human trial results were formally published in February 2024.[19]

Table 2: Summary of Clinical Trial NCT04431219 (LIS1 in Kidney Transplantation)

Feature	Details	Reference(s)
Trial Identifier	NCT04431219	16
Phase	Phase 1/2 (First-in-Human, Dose Escalation)	4
Study Title	First in Human Study for the Assessment of Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of LIS1 in Kidney Transplanted Patients	17
Patient Population	Primary kidney transplant recipients; low/medium immunologic risk (n=10 total across cohorts)	4
Intervention	LIS1 administered intravenously for 5 days; dose escalation from 0.6 mg/kg to 10 mg/kg	4
Primary Endpoints	Safety, Tolerability, Pharmacokinetics (PK), Pharmacodynamics (PD), Immunogenicity	4
Key Safety Findings	Well tolerated; no Cytokine Release Syndrome (CRS); no severe thrombocytopenia or leukopenia reported	4
Key Efficacy/PD Findings	CD3+ T-cell depletion to <100/mm³ with doses $\geq$6mg/kg; rapid lymphocyte recovery (2-4 weeks)	4
Immunogenicity	No anti-LIS1 antibodies detected	4
Key PK Findings	Terminal half-life (T1/2​) = 33.7 days; linear disposition	4
Overall Conclusion	Genome-edited swine-derived polyclonal LIS1 ALG was well tolerated, did not elicit antidrug antibodies, and caused time-limited T-cell depletion.	4

B. Emerging Indication: Lymphoproliferative T-cell Disorders / Peripheral T-Cell Lymphoma (PTCL)

Beyond transplantation, Xenothera is leveraging its GH-pAb platform to develop therapeutics for oncology, with a specific focus on T-cell malignancies such as Peripheral T-Cell Lymphoma (PTCL).[9] PTCLs represent a heterogeneous group of aggressive non-Hodgkin lymphomas with generally poor prognoses and significant unmet medical needs, as current treatments often have limited efficacy.[21]

Product Nomenclature: LIS1 vs. LIS22

Xenothera's pipeline explicitly lists a product named "LIS22" for T-cell lymphoma. LIS22 is described as targeting multiple markers on T-lymphoma cells and binding to up to 90% of patient tumor cells.[9] LIS22 has received Orphan Drug Designations from the FDA (2023) and EMA (2024) for PTCL.[20]

However, the clinical trial NCT06495723 (PALT1), which is investigating a GH-pAb for PTCL, refers to the investigational drug as "LIS1".[23] This raises a point of potential ambiguity: "LIS1" in the PALT1 trial could be an earlier designation for the product now more specifically identified as LIS22, or it could imply that the original LIS-1 (DB18388) formulation developed for transplantation is also being evaluated for this oncologic indication. For the purpose of this report, the nomenclature as presented in the source materials for each context (transplantation vs. oncology trial) will be used, while acknowledging this potential overlap. The underlying therapeutic strategy—targeting and depleting T-cells—is common to both applications, repurposed for an oncologic context where the T-cells are malignant. The polyclonal nature of such an antibody could be advantageous in targeting the diverse and heterogeneous cell populations often found in cancers.

Clinical Trial NCT06495723 (PALT1)

• Study Title: "Polyspecific Antibodies in Lymphoproliferative T-cell Disorders (PALT1)".[24]
• Drug: LIS1.[23]
• Sponsor: Xenothera SAS.[23]
• Phase: This is a Phase 1/2 trial. Part 1 is a dose-escalation phase to determine the Maximum Tolerated Dose (MTD) and/or Recommended Part 2 Dose (RP2D) of LIS1 as a single agent. Part 2 is an expansion phase to investigate the anti-tumor efficacy of LIS1 in selected subtypes of PTCL.[20]
• Status: The trial is actively recruiting patients.[20] The first patient was recruited in July/August 2024.[20]
• Target Enrollment: 54 participants.[23]
• Locations: The trial is being conducted in multiple centers in France, including CHU de Caen, CHU de Clermont-Ferrand, and CHU Henri-Mondor.[23] Initially, five French centers were involved.[22]
• Objectives (Part 1): To establish the MTD or RP2D of LIS1 monotherapy.[24]
• Objectives (Part 2): To investigate the anti-tumor efficacy of LIS1 in specific PTCL subtypes.[24]
• Eligibility Criteria (selected): Adult patients (≥18 years) with a histological diagnosis of relapsed or refractory PTCL, according to the WHO 2022 classification of lymphoid neoplasms (various subtypes included).[24]
• Dosage Cohorts: The trial initiated with a patient at a 2mg dose, followed by a 4mg cohort, with plans for a subsequent 6mg cohort.[20]
• Preclinical Rationale: The product LIS22 (potentially the same agent as LIS1 in PALT1) demonstrated potent anti-tumoral activity against cancer lymphocyte cell lines and achieved up to 90% reduction in tumor size in preclinical in vivo models.[21]

The successful demonstration of safety and efficacy of a GH-pAb like LIS1/LIS22 in PTCL would represent a significant therapeutic advance for this challenging disease and would further validate the versatility of Xenothera's GH-pAb technology platform, extending its application from immunosuppression into the domain of onco-hematology. The precise structural and functional relationship between LIS-1 (DB18388 for transplantation), LIS1 (as designated in the PALT1 trial), and LIS22 (Xenothera's pipeline name for the T-cell lymphoma product) warrants definitive clarification from the developer for precise scientific discourse.

Table 3: Overview of Clinical Trial NCT06495723 (PALT1 - LIS1 in PTCL)

Feature	Details	Reference(s)
Trial Identifier	NCT06495723 (PALT1)	23
Drug	LIS1	23
Sponsor	Xenothera SAS	23
Phase	Phase 1/2	23
Study Title	Polyspecific Antibodies in Lymphoproliferative T-cell Disorders	24
Indication	Relapsed/Refractory Peripheral T-Cell Lymphoma (PTCL)	24
Status	Recruiting	20
Key Objectives	Determine MTD/RP2D (Part 1); Evaluate anti-tumor efficacy (Part 2)	24
Dosage	Dose escalation; cohorts include 2mg, 4mg, 6mg	20

VII. Manufacturing and Developer Insights

Developer

LIS-1 and related GH-pAbs are developed by XENOTHERA SAS, a biotechnology company headquartered in Nantes, France.[14] Xenothera specializes in leveraging its glyco-humanized polyclonal antibody platform for various therapeutic areas, including transplantation, oncology, and infectious diseases.[9]

Production Technology: Glyco-Humanized Polyclonal Antibodies (GH-pAb)

LIS-1 is a product of Xenothera's proprietary GH-pAb technology platform.[2] This platform is central to the unique characteristics of LIS-1.

• Source Animals and Genetic Modification: The antibodies are produced by immunizing swine that have been genetically engineered to be double knockouts (DKO) for two key genes: GGTA1 (encoding α-1,3-galactosyltransferase) and CMAH (encoding cytidine monophosphate-N-acetylneuraminic acid hydroxylase).[4] The absence of these enzymes results in the lack of $\alpha$Gal and Neu5Gc carbohydrate xenoantigens on the surface of the swine's cells and, crucially, on the polyclonal antibodies they produce.[5] This "glyco-humanization" process is designed to prevent the antibodies from being recognized as foreign by the human immune system, thereby reducing the risk of eliciting anti-drug antibodies, serum sickness, and allergic reactions that are common with conventional animal-derived serum products.[11]
• Fc Engineering: In addition to the removal of carbohydrate xenoantigens, there is an indication that LIS1 (GH-ALG) is "Fc-silenced in humans".[7] This suggests that the Fc portion of the swine IgG may undergo further engineering or selection to minimize its interaction with human Fc receptors, particularly those involved in ADCC. This aligns with the observation that LIS-1's mechanism of action excludes ADCC.[2] This dual approach—glycan modification and potential Fc protein engineering—represents a sophisticated strategy to optimize both the immunogenicity and effector function profile of the therapeutic antibody.
• Purification: Following immunization and serum collection from these DKO swine, the IgG fraction is extracted and purified. The process is generally described as involving "capture and polishing chromatography" to obtain the whole IgG fraction.[18] More broadly, polyclonal antibody purification typically involves initial clarification steps (centrifugation or filtration) followed by affinity chromatography (e.g., using Protein A or Protein G, which bind to the Fc region of IgG, or antigen-specific affinity columns) and potentially further polishing steps like gel filtration chromatography to achieve high purity and formulate the final product.[12]
• Dedicated Production Facilities: Recognizing the critical importance of a consistent and controlled source of these specialized animals, Xenothera established a high-biosafety "pharmaceutical farm" in 2022. This facility is specifically designed for the breeding of the genetically modified DKO pigs required for the production of their GH-pAbs.[25] This investment in vertical integration, controlling the source animal supply chain, is a significant strategic move. It ensures the quality, scalability, and potentially the cost-effectiveness of GH-pAb manufacturing, which could provide a substantial competitive edge if these therapies gain market approval.

VIII. Regulatory Status

LIS-1 and its related GH-pAb counterparts have achieved significant regulatory milestones, underscoring their therapeutic potential.

Orphan Drug Designations

Orphan Drug Designation (ODD) is granted to therapies intended for rare diseases or conditions, providing incentives to the developer such as market exclusivity and assistance during the development process.

• For Solid Organ Transplantation (LIS1):
• The FDA granted ODD to LIS1 for solid organ transplantation in 2020.[9]
• The EMA followed suit, granting ODD for LIS1 in solid organ transplantation in June/July 2022.[9]
• For T-cell Lymphoma / Peripheral T-Cell Lymphoma (LIS22/LIS1):
• The FDA granted ODD to LIS22 for PTCL in 2023.[9]
• The EMA granted ODD for the antibody (LIS22/LIS1) in PTCL in June 2024.[20]

The attainment of ODDs from both major regulatory agencies for two distinct therapeutic indications highlights the recognized unmet medical need in these areas and the perceived potential of Xenothera's GH-pAb technology to provide a significant benefit to patients. This dual regulatory validation can also serve to accelerate the development pathways and attract further investment.

Current Development Phase

• LIS1 (Solid Organ Transplantation): The Phase 1/2 clinical trial (NCT04431219) in kidney transplant recipients was completed in 2022.[17]
• LIS1/LIS22 (Peripheral T-Cell Lymphoma): The Phase 1/2 clinical trial (PALT1, NCT06495723) is currently recruiting patients.[20]

Future Clinical and Regulatory Plans

• LIS1 (Solid Organ Transplantation): Xenothera has indicated plans for a confirmatory Phase II/III trial for LIS1 in solid organ transplantation, which was anticipated to commence following the initial Phase 1/2 study.[14]
• LIS22 (Peripheral T-Cell Lymphoma): The company aims to seek early access authorization for LIS22 in PTCL in France and Europe by 2027, contingent on successful trial outcomes.[21]

The parallel pursuit of regulatory approvals and clinical development for both transplantation and oncology indications demonstrates a strategic diversification of Xenothera's core GH-pAb technology. This approach leverages the fundamental advantages of the platform—primarily reduced immunogenicity and effective T-cell targeting—for distinct disease contexts, potentially maximizing its therapeutic utility.

IX. Discussion and Expert Analysis

Synthesis of LIS-1's Profile: Strengths and Potential Limitations

Based on the available preclinical and early clinical data, LIS-1 (DB18388) and its related GH-pAb constructs exhibit several notable strengths:

• Reduced Immunogenicity: The most significant advantage is the markedly reduced immunogenicity, evidenced by the lack of detectable anti-LIS1 antibodies in the Phase 1 kidney transplant trial.[4] This is a direct outcome of the glyco-humanization strategy.
• Favorable Tolerability: Early clinical data suggest LIS-1 is well tolerated, without reports of severe cytokine release syndrome or significant hematological toxicities often associated with older polyclonal antibody therapies.[4]
• Controlled Immunomodulation: LIS-1 achieves effective T-cell depletion necessary for induction therapy but allows for rapid lymphocyte recovery (within 2-4 weeks in humans).[4] This "time-limited T-cell depletion" profile may reduce the duration of high susceptibility to infections.
• Differentiated Mechanism of Action: The exclusion of ADCC and potential sparing of T-regulatory cells (observed preclinically) represent mechanistic distinctions that could translate into an improved safety profile and a more favorable long-term immune balance.[2]
• Regulatory Support: Multiple Orphan Drug Designations from the FDA and EMA for different indications validate its potential.[9]
• Validated Production Platform: The underlying GH-pAb technology, including the establishment of dedicated breeding facilities for DKO swine, appears robust.[25]

Potential limitations or areas requiring further elucidation include:

• Development Stage: LIS-1 is still in clinical development. Long-term efficacy (e.g., impact on chronic rejection, long-term graft survival) and comprehensive safety data in larger, more diverse patient populations are pending.
• T-reg Sparing in Humans: Confirmation of T-regulatory cell sparing in human clinical trials and its clinical significance is needed.
• Structural Details: Precise, publicly available structural details of the polyclonal antibody mixture are limited, which is common for such biologics but means reliance on functional and manufacturing consistency.[1]
• Nomenclature: The potential for confusion between LIS-1 (DB18388 for transplantation), LIS1 (as used in the PALT1 oncology trial), and LIS22 (pipeline name for oncology) needs clarification from the developer for precise scientific communication.

Potential Impact on Current Treatment Paradigms

• Solid Organ Transplantation: LIS-1 has the potential to become a preferred induction agent if further trials confirm its favorable safety, reduced immunogenicity, and effective immunosuppression. It could replace or offer a superior alternative to conventional ATGs, particularly in patients at higher risk of complications from existing agents or where long-term immunomodulation with minimal sensitization is desired.[7] The low immunogenicity (no anti-drug antibodies detected [4]) is particularly noteworthy, as it could uniquely position LIS-1 for scenarios requiring intermittent or repeated courses of T-cell depletion. This is often problematic with traditional, more immunogenic ATGs due to the risk of sensitization, which can render re-treatment ineffective or dangerous. The ability to re-administer LIS-1 without significant immunogenic consequences could open new therapeutic strategies in managing recurrent or chronic rejection episodes, or in certain autoimmune conditions requiring pulsed T-cell targeted therapy.
• Peripheral T-Cell Lymphoma: For PTCL, a group of diseases with limited effective treatments and poor outcomes, LIS1/LIS22 could offer a novel therapeutic modality if it demonstrates significant anti-tumor activity and manageable toxicity in ongoing trials.[21]

Unmet Needs Addressed and Remaining Questions

LIS-1 aims to address the critical unmet need for safer, less immunogenic, and more precisely acting immunosuppressive agents in transplantation. In oncology, it targets the urgent need for new therapies for aggressive T-cell lymphomas.

Key remaining questions include:

• What is the long-term impact of LIS-1 induction on graft survival, rates of chronic rejection, and overall patient outcomes in transplant recipients?
• What is the full spectrum of adverse effects when LIS-1 is used in larger and more diverse patient populations, including those with more complex co-morbidities?
• Is the T-reg sparing effect observed preclinically consistently replicated in human subjects, and what is its clinical significance in promoting long-term tolerance?
• What are the optimal dosing regimens and durations of therapy for LIS-1 in different transplantation settings (e.g., kidney, heart, lung) and for PTCL?
• What is the definitive relationship (structural and functional) between the LIS-1 product used in transplantation (DB18388), the LIS1 product in the PALT1 trial, and the LIS22 product designated for T-cell lymphoma in Xenothera's pipeline?

Considerations for Future Research and Development

Future development should prioritize:

• Conducting robust, adequately powered Phase III trials in transplantation, ideally with head-to-head comparisons against current standard-of-care induction agents.
• Continued evaluation in Phase II/III trials for PTCL to establish efficacy and further define the safety profile.
• Incorporating detailed immunological monitoring in clinical trials, focusing on T-cell subset dynamics (including effector, memory, and regulatory T-cells), B-cell responses, and overall immune reconstitution patterns.
• Exploring the potential of LIS-1 or similar GH-pAbs in other T-cell mediated autoimmune diseases or inflammatory conditions where targeted, transient T-cell modulation might be beneficial.

The development trajectory of LIS-1 (GH-ALG) serves as a compelling example of "biobetter" engineering. It involves taking an established therapeutic concept—polyclonal anti-lymphocyte therapy—and systematically addressing its known deficiencies, primarily immunogenicity and non-specific or overly prolonged depletion, through the application of advanced biotechnology, including the genetic engineering of source animals and potentially Fc region modifications.

X. Conclusion

LIS-1 (DB18388) is an investigational glyco-humanized polyclonal antibody that represents a promising next-generation immunomodulatory agent. Its development is founded on an innovative approach to mitigate the immunogenicity associated with traditional animal-derived anti-lymphocyte globulins by utilizing genetically engineered DKO swine as the antibody source. Early clinical trial data in kidney transplantation (NCT04431219) have demonstrated a favorable safety and tolerability profile, an absence of detectable anti-drug antibodies, and effective, time-limited T-cell depletion with rapid lymphocyte recovery. These findings suggest that LIS-1 could offer a significant improvement over existing induction therapies in solid organ transplantation.

Furthermore, the exploration of LIS1/LIS22 in aggressive T-cell malignancies, such as Peripheral T-Cell Lymphoma (NCT06495723), highlights the versatility of Xenothera's GH-pAb platform. The distinct mechanism of action, which includes complement-mediated cytotoxicity, phagocytosis, apoptosis, and antigen masking, while excluding ADCC and potentially sparing T-regulatory cells, further differentiates LIS-1 from older polyclonal therapies.

While LIS-1 is still under clinical investigation and long-term efficacy and safety data are awaited, it stands as a significant advancement in polyclonal antibody therapeutics. Pending successful outcomes in ongoing and future larger-scale clinical trials, LIS-1 has the potential to become a valuable therapeutic option, improving outcomes for patients undergoing solid organ transplantation and possibly offering new hope for individuals with difficult-to-treat T-cell cancers. Its development underscores the power of targeted bioengineering to refine and enhance existing therapeutic modalities.

XI. References

[1]

Works cited

1. LIS-1: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed May 28, 2025, https://go.drugbank.com/drugs/DB18388
2. LIS1, a glyco-humanized swine polyclonal anti-lymphocyte globulin, as a novel induction treatment in solid organ transplantation, accessed May 28, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9978386/
3. LIS1, a glyco-humanized swine polyclonal anti-lymphocyte globulin, as a novel induction treatment in solid organ transplantation - Frontiers, accessed May 28, 2025, https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1137629/full
4. First-in-human Study With LIS1, a Next-generation Porcine Low Immunogenicity Antilymphocyte Immunoglobulin in Kidney Transplantation | Request PDF - ResearchGate, accessed May 28, 2025, https://www.researchgate.net/publication/378596153_First-in-human_Study_With_LIS1_a_Next-generation_Porcine_Low_Immunogenicity_Antilymphocyte_Immunoglobulin_in_Kidney_Transplantation
5. (PDF) LIS1, a glyco-humanized swine polyclonal anti-lymphocyte globulin, as a novel induction treatment in solid organ transplantation - ResearchGate, accessed May 28, 2025, https://www.researchgate.net/publication/368586729_LIS1_a_glyco-humanized_swine_polyclonal_anti-lymphocyte_globulin_as_a_novel_induction_treatment_in_solid_organ_transplantation
6. LIS1, a glyco-humanized swine polyclonal anti-lymphocyte globulin, as a novel induction treatment in solid organ transplantation - PubMed, accessed May 28, 2025, https://pubmed.ncbi.nlm.nih.gov/36875084/
7. LIS1, a glyco-humanized swine polyclonal anti-lymphocyte globulin, as a novel induction treatment in solid organ transplantation | bioRxiv, accessed May 28, 2025, https://www.biorxiv.org/content/10.1101/2022.09.08.507114.full
8. www.biorxiv.org, accessed May 28, 2025, https://www.biorxiv.org/content/10.1101/2022.09.08.507114v1.full-text#:~:text=The%20novel%20therapeutic%20modality%20of,adequate%20immunosuppression%20and%20reducing%20immunogenicity.
9. Pipeline - XENOTHERA, accessed May 28, 2025, https://www.xenothera.com/attractive-pipeline/
10. XAV-19, a novel swine glyco-humanized polyclonal antibody against SARS-CoV-2 spike - XENOTHERA, accessed May 28, 2025, https://www.xenothera.com/wp-content/uploads/2021/04/BioRxiv-XAV-19-active-on-SARS-CoV-2-variants-April21.pdf
11. Anti-SARS-CoV-2 glyco-humanized polyclonal antibody XAV-19: phase II/III randomized placebo-controlled trial shows acceleration to recovery for mild to moderate patients with COVID-19, accessed May 28, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11061480/
12. LIS1 Antibody | Cell Signaling Technology, accessed May 28, 2025, https://www.cellsignal.com/products/primary-antibodies/lis1-antibody/12453
13. Anti-LIS1 antibody [EPR3335(2)] (ab109630) - Abcam, accessed May 28, 2025, https://www.abcam.com/en-us/products/primary-antibodies/lis1-antibody-epr33352-ab109630
14. Orphan designation by the European Medicines Agency for LIS1, the transplant induction therapy from the pharmaceutical company X - XENOTHERA, accessed May 28, 2025, https://www.xenothera.com/wp-content/uploads/2022/10/UK-220711-XENOTHERA_EMA-LIS1-Press-release.pdf
15. How to generate antibodies by immunizing animals with an antigen (immunogen) - MBL Life Science, accessed May 28, 2025, https://www.mblbio.com/bio/g/support/method/antibody-production.html
16. First-in-human Study With LIS1, a Next-generation Porcine Low Immunogenicity Antilymphocyte Immunoglobulin in Kidney Transplantation - PubMed, accessed May 28, 2025, https://pubmed.ncbi.nlm.nih.gov/38421879/
17. Clinical trials - XENOTHERA, accessed May 28, 2025, https://www.xenothera.com/clinical-trials/
18. XAV-19, a Swine Glyco-Humanized Polyclonal Antibody Against SARS- CoV-2 Spike Receptor - NET, accessed May 28, 2025, https://rcastoragev2.blob.core.windows.net/4898b6bd2eb6c4903ebda32439733e6f/PMC8634597.pdf
19. Newsroom – XENOTHERA, accessed May 28, 2025, https://www.xenothera.com/news/
20. XENOTHERA reaches important milestones in its oncology and onco-hematology clinical trials., accessed May 28, 2025, https://www.xenothera.com/2025/01/15/xenothera-reaches-important-milestones-in-its-oncology-and-onco-hematology-clinical-trials/
21. XENOTHERA successfully secures €4 Million non-dilutive financing from the France 2030 Public Investment Plan for its LIS22 treatment for peripheral T-Cell lymphoma., accessed May 28, 2025, https://www.xenothera.com/2025/01/15/xenothera-successfully-secures-e4-million-non-dilutive-financing-from-the-france-2030-public-investment-plan-for-its-lis22-treatment-for-peripheral-t-cell-lymphoma/
22. XENOTHERA ANNOUNCES THE RECRUITMENT OF THE FIRST PATIENT OF THE PALT1 TRIAL IN PERIPHERAL T-CELL LYMPHOMA (PTCL) AND ITS ORPHAN DRUG STATUS (ODD) BY THE EMA, accessed May 28, 2025, https://www.xenothera.com/2024/10/10/xenothera-announces-the-recruitment-of-the-first-patient-of-the-palt1-trial-in-peripheral-t-cell-lymphoma-ptcl-and-its-orphan-drug-status-odd-by-the-ema/
23. LIS-1 | MedPath, accessed May 28, 2025, https://trial.medpath.com/drug/4a8618a3670c2562
24. Polyspecific Antibodies in Lymphoproliferative T-cell Disorders - ClinicalTrials.Veeva, accessed May 28, 2025, https://ctv.veeva.com/study/polyspecific-antibodies-in-lymphoproliferative-t-cell-disorders
25. XENOTHERA Welcomes the National Academy of Medicine's Call for a National Xenotransplantation Plan and Reaffirms Its Commitment to This Breakthrough Medical Innovation, accessed May 28, 2025, https://www.xenothera.com/2025/05/22/xenothera-welcomes-the-national-academy-of-medicines-call-for-a-national-xenotransplantation-plan-and-reaffirms-its-commitment-to-this-breakthrough-medical-innovation/
26. Anti-LIS1 antibody, Mouse monoclonal (L7391) - Sigma-Aldrich, accessed May 28, 2025, https://www.sigmaaldrich.com/deepweb/assets/sigmaaldrich/product/documents/372/652/l7391dat.pdf
27. Anti-LIS1 antibody (ab117457) - Abcam, accessed May 28, 2025, https://www.abcam.com/en-us/products/primary-antibodies/lis1-antibody-ab117457
28. LIS1 Polyclonal antibody - Proteintech, accessed May 28, 2025, https://www.ptglab.com/Products/Pictures/pdf/20678-1-AP.pdf
29. LIS1 Polyclonal Antibody (PA5-82710) - Thermo Fisher Scientific, accessed May 28, 2025, https://www.thermofisher.com/antibody/product/LIS1-Antibody-Polyclonal/PA5-82710