OR-502: A Novel LILRB2-Targeting Monoclonal Antibody for Cancer Immunotherapy – Preclinical Rationale and Emerging Clinical Profile

1. Introduction to OR-502: A Novel LILRB2-Targeting Immunotherapy

1.1. Overview of OR-502 and its Developer, OncoResponse

OR-502 is an investigational humanized immunoglobulin G1 (IgG1) monoclonal antibody currently under clinical development for the treatment of various cancers.[1] It is engineered to specifically target the Leukocyte Immunoglobulin-like Receptor Subfamily B Member 2 (LILRB2), an inhibitory immune checkpoint receptor also known by other designations such as ILT4 (Immunoglobulin-Like Transcript 4), LIR2 (Leukocyte Immunoglobulin-like Receptor 2), or CD85d.[1] The compound is also identified by the code name OR 502.[1]

The development of OR-502 is being spearheaded by OncoResponse, Inc., a clinical-stage biotechnology company with a distinct focus on discovering and advancing immunotherapies.[3] OncoResponse's foundational discovery strategy revolves around interrogating the immune systems of "Elite Cancer Responders"—patients who exhibit exceptional and durable responses to existing checkpoint inhibitor therapies. The company employs a proprietary B-cell technology platform to identify and isolate novel antibodies from these elite responders, particularly targeting components of the tumor microenvironment (TME) associated with immunosuppressive myeloid cell biology.[3] This approach is predicated on the hypothesis that the immune systems of such patients have naturally generated highly effective antibodies against critical tumor or immune targets. By harnessing these "naturally optimized" human antibodies, OncoResponse aims to develop therapeutics with potentially superior efficacy and safety profiles compared to antibodies derived through more conventional methodologies.

The characteristics of OR-502 are summarized in Table 1.

Table 1: OR-502 Key Characteristics

Characteristic	Description
Investigational Name	OR-502
Synonyms	OR 502, anti-LILRB2 monoclonal antibody OR502, anti-ILT4 monoclonal antibody OR502
Drug Type	Humanized IgG1 monoclonal antibody
Target	Leukocyte Immunoglobulin-like Receptor Subfamily B Member 2 (LILRB2); also known as ILT4, LIR2, CD85d
Developer	OncoResponse, Inc.
Key Mechanism of Action	LILRB2 antagonist; blocks LILRB2 interaction with HLA class I ligands; modulates myeloid cell function (reprograms immunosuppressive myeloid cells); enhances innate and adaptive anti-tumor immunity.

Data synthesized from.[1]

1.2. The LILRB2 Target: Role in Immune Evasion and Rationale for Inhibition

LILRB2 (ILT4) is a type I transmembrane glycoprotein belonging to the leukocyte immunoglobulin-like receptor (LILR) family, which plays a significant role in regulating immune cell activity.[1] It functions as an inhibitory immune checkpoint receptor and is predominantly expressed on the surface of various myeloid cell populations, including monocytes, macrophages (with notable expression on tumor-associated macrophages or TAMs), dendritic cells (DCs), and granulocytes.[1] While primarily found on myeloid cells, LILRB2 expression has also been detected on certain tumor cells.[1]

The interaction of LILRB2 with its ligands is a key mechanism through which tumors evade immune surveillance. Its ligands are primarily classical and non-classical Major Histocompatibility Complex (MHC) class I molecules, such as HLA-G, HLA-A, and HLA-B, which can be upregulated on the surface of cancer cells.[1] Upon engagement by these ligands, LILRB2 transduces inhibitory signals within the myeloid cells. These signals dampen the pro-inflammatory and anti-tumor functions of myeloid cells, such as antigen presentation, phagocytosis, and T-cell activation, thereby fostering an immunosuppressive TME that supports tumor growth and survival.[3] The clinical significance of this pathway is underscored by observations that elevated LILRB2 expression in the TME often correlates with poor prognosis and reduced survival in various cancer types.[3]

The therapeutic rationale for targeting LILRB2 with an antagonist antibody like OR-502 is to disrupt this axis of immune suppression. By blocking the inhibitory signals mediated by LILRB2, such therapies aim to "reprogram" or "re-educate" the immunosuppressive myeloid cells within the TME, shifting their phenotype towards a pro-inflammatory, anti-tumor state. This modulation is anticipated to enhance both innate immune responses (e.g., macrophage activity) and, critically, adaptive T-cell-mediated tumor destruction by creating a more permissive environment for T-cell function.[1] A potential outcome of this approach is the conversion of immunologically "cold" tumors (characterized by a lack of T-cell infiltration and an immunosuppressive milieu) into "hot" tumors (T-cell inflamed and more responsive to immunotherapy).[9] This strategy of targeting myeloid cell checkpoints offers a complementary approach to existing T-cell-focused immunotherapies, potentially overcoming resistance mechanisms and broadening the spectrum of patients who can benefit from cancer immunotherapy.

2. Mechanism of Action of OR-502

OR-502 employs a multi-faceted mechanism to counteract LILRB2-mediated immune suppression and enhance anti-tumor immunity. This involves specific binding to LILRB2, comprehensive blockade of its ligand interactions, subsequent reprogramming of myeloid cell function, and ultimately, the potentiation of both innate and adaptive immune responses.

2.1. Binding Characteristics and Specificity

OR-502 is a humanized IgG1 monoclonal antibody engineered to bind with high specificity and affinity to its target, LILRB2.[1] Preclinical characterization has revealed that OR-502 binds to a distinct epitope on the LILRB2 protein, which differentiates it from some other anti-LILRB2 antibodies currently in development or used as benchmarks.[11] This unique binding site is thought to be a contributor to its potentially superior functional profile.

The affinity of OR-502 for human LILRB2 is high, with a reported dissociation constant (KD​) of 1.18 nM. This binding affinity is notably stronger than that of a benchmark anti-LILRB2 antibody, 1E1, which has a reported KD​ of 3.33 nM.[4] Such higher affinity can translate to more potent and sustained target engagement at lower antibody concentrations. Furthermore, OR-502 demonstrates cellular specificity, binding to human myeloid cells such as monocytes, macrophages, and dendritic cells, which are the primary expressers of LILRB2, without exhibiting binding to lymphocyte populations.[4] This specificity is crucial for targeted immunomodulation within the TME while minimizing potential off-target effects on other immune cell lineages. The combination of a distinct binding epitope and high target affinity forms a strong basis for the "best-in-class" potential ascribed to OR-502 in preclinical evaluations when compared to other agents targeting the same pathway.[4]

2.2. Ligand Blockade and Interruption of Inhibitory Signaling

A cornerstone of OR-502's mechanism is its ability to effectively block the interaction between LILRB2 and its cognate ligands. These ligands predominantly include classical MHC class I molecules (such as HLA-A and HLA-B) and non-classical MHC class I molecules (such as HLA-G), which are frequently overexpressed on tumor cells as a means of immune evasion.[1] Preclinical data, including flow cytometry-based assays using HLA tetramers and cell-surface HLA-G, confirm that OR-502 antagonizes the binding of LILRB2 to these diverse ligands.[4]

By preventing this ligand-receptor engagement, OR-502 effectively interrupts the downstream inhibitory signaling cascade that LILRB2 activation would normally trigger within myeloid cells.[1] This abrogation of LILRB2-mediated negative signaling is critical for lifting the restraints on myeloid cell anti-tumor functions within the TME.[1] The capacity to broadly block interactions with multiple HLA ligands is a significant feature, as tumors may utilize a variety of these molecules to engage LILRB2. A comprehensive blockade by OR-502 is therefore more likely to result in a robust and complete neutralization of this key immunosuppressive pathway.

2.3. Modulation of Myeloid Cell Function and Cytokine Profile

Following ligand blockade, OR-502 actively modulates the functional state of LILRB2-expressing myeloid cells. It is designed to reprogram these cells, particularly immunosuppressive M2-like TAMs, shifting them from a tumor-permissive phenotype towards a pro-inflammatory, anti-tumor (e.g., M1-like) state.[3] This reprogramming involves preventing the generation of new suppressive macrophages and reversing the functional characteristics of existing M2-like TAMs within the TME.[4]

This functional shift is accompanied by a significant alteration in the cytokine milieu. Preclinical studies using human peripheral blood mononuclear cells (PBMCs) stimulated with lipopolysaccharide (LPS) have shown that OR-502 treatment leads to an enhanced production of the pro-inflammatory, Th1-polarizing cytokine interferon-gamma (IFN-γ).[1] Concurrently, OR-502 treatment results in a reduction of the immunosuppressive cytokine interleukin-10 (IL-10).[4] This cytokine shift is indicative of a transition towards a more potent anti-tumor immune environment.

An important and potentially differentiating aspect of OR-502's mechanism is related to its humanized IgG1 isotype. The Fc portion of an IgG1 antibody can engage activating Fc$\gamma$ receptors (Fc$\gamma$Rs) expressed on the surface of myeloid cells.[11] It is proposed that this co-engagement of activating Fc$\gamma$Rs by OR-502, upon its binding to LILRB2 on the same cell, provides an additional stimulatory signal. This dual action—LILRB2 inhibitory signal blockade combined with Fc$\gamma$R-mediated activation—may lead to a more profound and effective reprogramming of myeloid cells than LILRB2 antagonism alone. This is a departure from many checkpoint inhibitors that utilize Fc-silent isotypes to avoid effector functions, suggesting a tailored approach for myeloid cell targets where such effector functions can be beneficial.

2.4. Enhancement of Innate and Adaptive Anti-Tumor Immunity

The modulation of myeloid cells by OR-502 translates into a broader enhancement of both innate and adaptive anti-tumor immune responses. By activating myeloid cells, OR-502 boosts innate immune functions such as phagocytosis and the production of inflammatory mediators.[4]

More significantly, the reprogramming of myeloid cells creates a TME that is more conducive to adaptive T-cell responses. Preclinical evidence demonstrates that OR-502 relieves macrophage-mediated suppression of T-cell proliferation.[4] Furthermore, in co-culture systems with M2c macrophages, OR-502 treatment enhances the effector functions of CD8+ T cells, leading to increased secretion of IFN-γ and perforin, molecules critical for cytotoxic T-lymphocyte (CTL)-mediated tumor cell killing.[1]

Notably, OR-502 has shown the ability to restore the IFN-γ secretion capacity of exhausted T cells when these T cells are co-cultured with M2c macrophages.[4] T-cell exhaustion is a major mechanism of immune evasion and resistance to immunotherapy. While OR-502 does not directly target T-cells, its ability to alter the myeloid cell landscape appears to indirectly alleviate the suppressive signals that contribute to T-cell exhaustion, thereby rejuvenating T-cell anti-tumor activity.

2.5. Potential for Synergistic Activity with Other Immunotherapies

The mechanism of OR-502 strongly supports its use in combination with other immunotherapies, particularly T-cell checkpoint inhibitors like anti-PD-1 or anti-PD-L1 antibodies. Preclinical studies have provided direct evidence for this synergy. In co-culture models of M2c macrophages and exhausted T-cells, OR-502 significantly amplified the IFN-γ production induced by pembrolizumab, an anti-PD-1 antibody.[4]

This synergistic effect likely arises from the complementary actions of the two classes of inhibitors. While PD-1 blockade reinvigorates T-cells by targeting a T-cell intrinsic checkpoint, LILRB2 blockade with OR-502 addresses the myeloid-mediated immunosuppression in the TME. By "re-educating" TAMs and other myeloid cells, OR-502 can create a more pro-inflammatory environment that is less hostile to T-cell infiltration and function. This, in turn, may render tumors more susceptible to PD-1 blockade or overcome existing resistance to such therapies. The clinical development strategy for OR-502, which includes combination arms with the PD-1 inhibitor cemiplimab, is built upon this strong preclinical rationale.[3]

3. Preclinical Profile of OR-502

The preclinical development of OR-502 has encompassed a range of in vitro functional assays and in vivo tumor model studies, providing a comprehensive assessment of its activity and a strong rationale for its clinical translation. These studies have consistently highlighted OR-502's differentiated profile, often demonstrating superiority over benchmark anti-LILRB2 antibodies.

3.1. In Vitro Functional Activity Summary

The in vitro characterization of OR-502 has established its specific and potent interaction with LILRB2 and its subsequent impact on immune cell function:

• Binding Characteristics: OR-502 binds with high affinity (KD = 1.18 nM) to human LILRB2 expressed on myeloid cells, showing no cross-reactivity with lymphocyte populations. This affinity was superior to the benchmark antibody 1E1 (KD = 3.33 nM).[4]
• Ligand Blockade: The antibody effectively antagonizes the binding of LILRB2 to its key ligands, including HLA-G, HLA-A, and HLA-B, thereby interrupting the primary inhibitory signal.[4]
• Cytokine Modulation: In LPS-stimulated human PBMC assays, OR-502 demonstrated superior ability compared to other anti-LILRB2 antibodies (1E1, J19, B2-19-16) in enhancing the production of the pro-inflammatory cytokine IFN-γ and reducing the secretion of the immunosuppressive cytokine IL-10.[4] This shift indicates a favorable modulation of the immune microenvironment.
• Macrophage Reprogramming: OR-502 effectively prevents the generation of new immune-suppressive macrophages and can reprogram existing M2-like TAMs towards a more pro-inflammatory phenotype.[4]
• T-Cell Function Enhancement: In co-culture systems with M2c macrophages, OR-502 relieved the suppression of T-cell proliferation and significantly enhanced the secretion of IFN-γ and perforin by CD8+ T cells. Furthermore, it restored IFN-γ secretion by exhausted T cells in the presence of these suppressive macrophages.[4]
• Combination Synergy: OR-502 demonstrated significant synergistic activity with the anti-PD-1 antibody pembrolizumab in M2c/exhausted T-cell co-culture models, leading to amplified IFN-γ production by T-cells.[4]

The consistent outperformance of OR-502 across these varied functional assays provides robust preclinical evidence supporting its potential as a "best-in-class" LILRB2 antagonist. This differentiated profile is likely attributable to its unique binding epitope and the functional consequences of its IgG1 isotype, including potential Fc$\gamma$R co-engagement.

3.2. In Vivo Efficacy in Tumor Models

The in vivo anti-tumor activity of OR-502 was evaluated using a humanized mouse model. Specifically, the parental antibody of OR-502 was tested in NSG-SGM3 mice (which support human myeloid cell engraftment) bearing human SK-MEL-5 melanoma tumors.4

In this model, OR-502 monotherapy demonstrated significant anti-tumor efficacy, leading to both tumor growth inhibition and, notably, tumor regression. This effect was reported to be superior to that observed with the benchmark 1E1 anti-LILRB2 antibody in the same in vivo system.4

The achievement of tumor regression, rather than just stasis, with monotherapy in a humanized model is a strong preclinical signal. It suggests that OR-502 can effectively mobilize the human immune components present in the model to mount a significant attack against established tumors. These findings are particularly relevant given that melanoma is one of the tumor types being explored in the current clinical trial.

3.3. Pharmacokinetic Properties in Preclinical Models

Preclinical pharmacokinetic (PK) studies were conducted to assess the behavior of OR-502. In humanized FcRn mice, which are used to better predict human antibody half-life due to the role of the FcRn receptor in IgG recycling, OR-502 exhibited a half-life of approximately 10 days following a single 10 mg/kg intraperitoneal administration.4

This half-life is consistent with that of many therapeutic human IgG1 antibodies and supports the feasibility of clinically convenient dosing regimens, such as every two weeks (Q2W) or every three weeks (Q3W). The subsequent clinical trial design for OR-502 indeed utilizes a Q3W dosing schedule.10

A summary of these key preclinical findings is presented in Table 2.

Table 2: Summary of Key Preclinical Findings for OR-502

Category	Assay/Model	Key Finding	Comparator(s)	Source(s)
Binding Affinity	Surface Plasmon Resonance (SPR)	KD​ = 1.18 nM for LILRB2	1E1 (KD​ = 3.33 nM)	4
Ligand Blockade	Flow cytometry with HLA-tetramers/cells	Blocks LILRB2 binding to HLA-A, HLA-B, HLA-G	N/A	4
Cytokine Modulation	LPS-stimulated human PBMCs	Superior enhancement of IFN-γ; Superior reduction of IL-10	1E1, J19, B2-19-16	4
Macrophage Reprogramming	In vitro macrophage differentiation/function	Prevents/reverses M2-like suppressive phenotype	Benchmarks	4
T-Cell Co-culture	M2c macrophage / CD8+ or exhausted T-cell	Relieves T-cell suppression, ↑proliferation, ↑IFN-γ, ↑perforin; Restores exhausted T-cell IFN-γ	Benchmarks	4
Combination Synergy	M2c macrophage / exhausted T-cell + pembrolizumab	Significantly amplifies anti-PD-1 induced IFN-γ	Pembrolizumab alone	4
In Vivo Antitumor Activity	SK-MEL-5 tumor in humanized NSG-SGM3 mice	Significant tumor growth inhibition and regression; Superior to 1E1	1E1	4
Preclinical PK	Humanized FcRn mice (10 mg/kg IP)	t½ ~10 days	N/A	4

4. Clinical Development Program: The OR502-101 (NCT06090266) Study

The promising preclinical profile of OR-502 has led to its advancement into clinical trials. The cornerstone of its current clinical development is the OR502-101 study, registered under NCT06090266.

4.1. Study Design and Objectives

The OR502-101 trial (NCT06090266; Primary ID: OR502-101) is a first-in-human (FIH), Phase 1/2, open-label, multicenter study designed to evaluate OR-502 in patients with advanced solid tumors.[3] The study initiated patient dosing in November 2023.[3]

The study is structured in two main parts:

• Part A (Dose Escalation): This initial phase aimed to determine the safety, tolerability, maximum-tolerated dose (MTD), maximum achievable dose, or optimal biological dose of OR-502 for subsequent evaluation. Part A enrolled approximately 40 to 48 subjects across two arms:
• Arm A1: OR-502 administered as an intravenous (IV) monotherapy, with escalating doses of 100 mg, 200 mg, 400 mg, 800 mg, and 1600 mg, given once every three weeks (Q3W).[10]
• Arm A2: OR-502 administered IV Q3W at the same escalating dose levels in combination with a standard dose of cemiplimab, an anti-PD-1 antibody.[10] The dose escalation component of Part A is reported as complete.[10]
• Part B (Dose Expansion): This phase is designed to further evaluate the safety, tolerability, and preliminary anti-tumor activity of OR-502 at dose levels selected based on data from Part A. The initially selected dose for the mini-expansion cohorts is 800 mg Q3W.[10] Part B includes cohorts evaluating OR-502 both as monotherapy and in combination with cemiplimab in specific tumor types.[3] These cohorts include patients with previously treated platinum-resistant ovarian cancer (PROC), cutaneous squamous cell carcinoma (CSCC) [6], PD-(L)1 pretreated cutaneous melanoma (receiving OR-502 monotherapy), and PD-(L)1 pretreated non-small cell lung cancer (NSCLC) (receiving OR-502 in combination with cemiplimab).[6]

The primary objectives of the OR502-101 study encompass:

• Evaluation of the safety and tolerability of OR-502 administered as a monotherapy and in combination with cemiplimab.
• Determination of the MTD and/or Recommended Phase 2 Dose (RP2D) of OR-502.
• Characterization of the pharmacokinetic (PK) profile and peripheral receptor occupancy (RO) of LILRB2 by OR-502.[3]

Secondary objectives (inferred from study descriptions as explicit outcome measure lists were not fully available in the provided materials) likely include:

• Assessment of the preliminary anti-tumor activity of OR-502 (monotherapy and combination), potentially measured by Objective Response Rate (ORR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Overall Survival (OS).
• Evaluation of pharmacodynamic (PD) markers to understand the biological effects of OR-502.[3]

A notable feature of the OR502-101 study is its adaptive design. The protocol incorporates elements that allow for flexibility in response to emerging data and evolving regulatory guidance, such as the FDA's Project Optimus initiative, which emphasizes comprehensive dose-finding and optimization early in oncology drug development. This adaptability has facilitated modifications, such as the introduction of mini-expansion cohorts for melanoma and NSCLC, without requiring formal protocol amendments, thereby enabling more rapid and efficient decision-making in the drug development process.[10]

As of April 2025, the dose escalation phase (Part A) was complete, and the mini-expansion cohorts in cutaneous melanoma and NSCLC were actively recruiting patients.[10] The overall status of the trial is listed as "Recruiting" for specific cohorts.[2]

The adaptive nature of this trial, combined with its dual focus on monotherapy and combination therapy from an early stage, reflects a contemporary and efficient strategy for clinical development. This approach is particularly pertinent in the competitive immuno-oncology landscape, where rapid generation of robust data on safety, PK/PD, and preliminary efficacy across various contexts is essential for guiding further development and positioning novel agents like OR-502.[9]

4.2. Patient Population and Eligibility Criteria

The OR502-101 trial enrolls adult patients (aged ≥18 years) with histologically confirmed advanced solid tumors, including carcinomas, sarcomas, or melanomas, that are either metastatic or locally advanced and not amenable to curative local therapy.[6]

For the initial dose-escalation phase (Part A) and the general expansion cohort (Cohort B1), eligible patients typically must have experienced disease progression on, or have been intolerant to, or considered ineligible for, established standard systemic anti-cancer therapies, with no available proven curative or life-prolonging treatment options.[14]

Specific eligibility criteria apply to the tumor-specific expansion cohorts in Part B:

• Cohorts B2-B3: Patients with cutaneous squamous cell carcinoma (CSCC) or previously treated platinum-resistant ovarian cancer (PROC) with advanced/metastatic disease.[6]
• Mini-expansion Cohorts (e.g., B4 - Cutaneous Melanoma, B5 - NSCLC): These cohorts focus on patients whose disease has progressed following at least 12 weeks of prior PD-(L)1 inhibitor-based therapy. Patients must have received at least two prior lines of treatment, with a preference for second-line patients after PD-(L)1 failure in the NSCLC cohort.[10]

Other key inclusion criteria generally include an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 [14], measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) [6], and adequate organ function.[6]

Key exclusion criteria are comprehensive and aim to ensure patient safety and the interpretability of trial results. These typically include:

• Known severe hypersensitivity reactions to other monoclonal antibody therapies.[14]
• Limited life expectancy (e.g., < 12 weeks).[14]
• Active and unstable central nervous system (CNS) primary tumors or metastases, or carcinomatous meningitis. Patients with previously treated and stable brain metastases may be eligible under specific conditions (e.g., clinically stable for ≥4 weeks, no new or enlarging lesions, off or on stable low-dose steroids).[6]
• Prior organ or allogeneic stem cell transplantation.[14]
• History of other malignancies, unless the patient has been disease-free for at least 3 years (with exceptions for certain adequately treated non-melanoma skin cancers or in situ cancers).[6]
• Recent or ongoing serious or uncontrolled infections, including viral (e.g., uncontrolled HIV, active HBV unless treated and DNA undetectable, active HCV unless treated and PCR negative), bacterial, or fungal infections. Active or latent tuberculosis is also an exclusion.[6]
• Recent use of systemic corticosteroids (e.g., >10 mg prednisone equivalent per day within 15 days prior to study commencement) or other immunosuppressive drugs.[6]

The focus on enrolling patients with advanced, refractory solid tumors, particularly those who have progressed after prior PD-(L)1 inhibitor therapy, is strategically significant. This patient population represents a high unmet medical need. Demonstrating activity in such heavily pre-treated individuals, especially in the immunotherapy-refractory setting, would underscore the potential of OR-502 to overcome existing resistance mechanisms and offer a valuable new therapeutic option.

4.3. Intervention: OR-502 Monotherapy and Combination with Cemiplimab

In the OR502-101 trial, OR-502 is administered as an intravenous (IV) infusion.[11] The dosing schedule for OR-502 is once every three weeks (Q3W).[10]

During the dose-escalation phase (Part A), patients received OR-502 at escalating dose levels of 100 mg, 200 mg, 400 mg, 800 mg, and 1600 mg.[10] Based on the safety, efficacy, PK, and RO data from Part A, a dose of 800 mg IV Q3W was selected for the initial mini-expansion cohorts in Part B.[10] The original design for Part B considered evaluating two separate dose levels of OR-502.[3]

In the combination arms of the study, OR-502 is administered with cemiplimab, an anti-PD-1 antibody. Cemiplimab is given at its standard dose, typically 350 mg IV Q3W, consistent with its approved labeling for various indications.[3] The choice of cemiplimab as the PD-1 inhibitor partner is logical, given the robust preclinical data demonstrating synergy between LILRB2 inhibition and PD-1 blockade.[4] Cemiplimab has an established efficacy and safety profile in several solid tumor types, including some targeted in the OR-502 trial (e.g., CSCC, NSCLC), providing a solid comparator background against which the contribution of OR-502 can be assessed. The congruent Q3W dosing schedules for both OR-502 and cemiplimab also facilitate practical administration in the clinical setting.

The selection of the 800 mg Q3W dose for OR-502 in the expansion cohorts was guided by a comprehensive evaluation of the data from the dose-escalation phase. This dose level was determined to provide a favorable balance of safety, tolerability, robust target engagement (as indicated by receptor occupancy), and preliminary signs of anti-tumor activity, aligning with the principles of identifying an optimal biological dose rather than simply the maximum tolerated dose.

An overview of the OR502-101 trial is provided in Table 3.

Table 3: Overview of the OR502-101 (NCT06090266) Clinical Trial

Parameter	Details
Official Title	A Study of OR502, a Monoclonal Antibody Targeting LILRB2, Alone and in Combination With Anticancer Agents 6
Phase	Phase 1/2
Study Design	Open-label, multicenter, first-in-human, dose-escalation (Part A) and dose-expansion (Part B)
Primary Objectives	Evaluate safety and tolerability of OR-502 (monotherapy and combination with cemiplimab); Determine MTD and/or RP2D of OR-502; Characterize PK and peripheral RO of OR-502.
Key Secondary Objectives	Preliminary anti-tumor activity (e.g., ORR, DCR); Pharmacodynamics.
Patient Population	Adults with advanced solid tumors (carcinoma, sarcoma, melanoma); Specific expansion cohorts for PROC, CSCC, PD-(L)1 pretreated cutaneous melanoma, PD-(L)1 pretreated NSCLC.
Interventions	OR-502 IV Q3W (escalating doses 100-1600mg in Part A; 800mg Q3W in mini-expansion); Cemiplimab 350mg IV Q3W (in combination arms).
Current Status (Apr 2025)	Dose escalation complete. Mini-expansion cohorts (cutaneous melanoma, NSCLC) recruiting. Overall status: Recruiting.
Estimated Enrollment	N=168 16
Key Dates	First patient dosed: November 2023.3

Data synthesized from.[2]

5. Emerging Clinical Data from OR502-101 (NCT06090266)

Early clinical data from the Phase 1 dose-escalation portion of the OR502-101 trial have provided initial insights into the safety, tolerability, anti-tumor activity, pharmacokinetics, and receptor occupancy of OR-502.

5.1. Safety and Tolerability Profile

OR-502 has demonstrated what has been described as an "excellent safety profile" in the FIH setting.[12] During the dose-escalation phase, the antibody was well tolerated when administered as monotherapy and in combination with cemiplimab, even up to the highest dose level tested, 1600 mg IV Q3W.[15]

Critically, no dose-limiting toxicities (DLTs) were reported across the dose range evaluated (100 mg to 1600 mg).[15] Furthermore, an update from November 2024 indicated that no serious adverse events (SAEs) or Grade $\geq$3 treatment-related adverse events (TRAEs) were observed at the maximum dose level.[15] This robust early safety signal is highly encouraging for a novel immunomodulatory agent. The absence of DLTs suggests a wide therapeutic window, which is advantageous for selecting an optimal biological dose for further development and for its potential use in combination regimens where overlapping toxicities can often be a concern. This favorable safety profile was a key factor in the decision to advance OR-502 to expansion cohorts.

5.2. Preliminary Anti-Tumor Activity

Early but "compelling" efficacy signals have been observed with OR-502 monotherapy in the dose-escalation phase, particularly in a heavily pre-treated patient population with advanced solid tumors.[15] Durable clinical responses with monotherapy have been confirmed.[10]

As of a November 2024 report on 17 evaluable subjects from the monotherapy dose escalation cohorts, the following anti-tumor activity was noted [15]:

• Partial Responses (PRs): Two patients achieved a PR.
• Stable Disease (SD): Nine patients achieved SD.
• Disease Control Rate (DCR): The DCR (PR + SD) was 65% (11 out of 17 patients).

Durable responses were specifically observed in patients with mucosal melanoma, non-small cell lung cancer (NSCLC), and dedifferentiated liposarcoma during this Phase 1 evaluation.[10] The observation of objective responses and a high DCR with OR-502 monotherapy in such a diverse and refractory patient population is a strong early indicator of its single-agent anti-tumor potential. This intrinsic activity is significant, suggesting that OR-502 can effectively modulate the immune system to combat cancer independently, providing a solid foundation for its further development both as a standalone agent and as a combination partner. The activity across different tumor histologies hints that its mechanism of action—myeloid cell reprogramming via LILRB2 blockade—may be broadly applicable to various cancers that utilize this pathway for immune evasion.

5.3. Clinical Pharmacokinetics (PK) and Receptor Occupancy (RO)

Pharmacokinetic and receptor occupancy data from the Phase 1 dose-escalation cohorts (both monotherapy and combination with cemiplimab) were presented at the American Association for Cancer Research (AACR) Annual Meeting in 2025.[11]

Pharmacokinetics:

OR-502 demonstrated approximately dose-proportional pharmacokinetics over the dose range of 100 mg to 1600 mg. The terminal half-life (t½) of OR-502 was reported to be in the range of 8 to 16 days. Specifically, in the monotherapy cohorts, the median t½ varied from 7.6 days at the 100 mg dose level to 15.9 days at the 1600 mg dose level. In the combination cohorts with cemiplimab, the median t½ ranged from 8.4 days (100 mg) to 12.4 days (1600 mg).11 Importantly, the co-administration of cemiplimab did not appear to alter the pharmacokinetic profile of OR-502.11 This predictable PK behavior, consistent with typical IgG1 antibodies, supports the Q3W dosing interval being utilized.

Receptor Occupancy:

Peripheral receptor occupancy of LILRB2 on myeloid cells (specifically classical monocytes and neutrophils) was measured by flow cytometry. The data indicated that near-complete RO was achieved at OR-502 doses of $\geq$200 mg, in both monotherapy and combination settings. For example, at the 200 mg monotherapy dose, the mean RO on classical monocytes was 96%, and on neutrophils, it was 89% at Cycle 2 Day 1 (C2D1). Similar high levels of RO were observed in the combination cohort (100% on classical monocytes and 94% on neutrophils at 200 mg C2D1).11 The presence of cemiplimab did not affect the RO of OR-502.11

The robust PK profile, characterized by dose-proportionality and a half-life suitable for Q3W administration, combined with the demonstration of near-complete peripheral LILRB2 target engagement at well-tolerated doses (≥200 mg), provides strong support for the selected 800 mg Q3W dose for the expansion phases. This dose is expected to ensure sustained and maximal biological effect by maintaining target saturation throughout the dosing interval.

Tables 4, 5, and 6 summarize the key reported clinical safety, preliminary efficacy, and PK/RO data, respectively.

Table 4: Summary of Reported Clinical Safety Data for OR-502 (NCT06090266 - Dose Escalation)

Dose Level / Cohort	Number of Patients (Approx.)	Dose-Limiting Toxicities (DLTs)	Serious Adverse Events (SAEs) (Treatment-Related)	Grade $\geq$3 TRAEs	Source(s)
Up to 1600 mg (Mono & Combo)	~40-48 total in escalation	None reported	None reported at max dose (as of Nov 2024)	None reported at max dose (as of Nov 2024)	10

Note: Detailed AE types and frequencies across all dose levels are not yet fully available in the provided snippets. Data as of Nov 2024 for highest dose.

Table 5: Summary of Reported Preliminary Clinical Efficacy Data for OR-502 (NCT06090266 - Monotherapy Dose Escalation)

Tumor Type(s)	Evaluable Patients (N)	Objective Response Rate (ORR)	Partial Responses (PRs)	Stable Disease (SD)	Disease Control Rate (DCR)	Notable Responding Tumor Types	Source(s)
Advanced Solid Tumors (heavily pre-treated)	17	11.8% (2/17)	2	9	65% (11/17)	Mucosal Melanoma, NSCLC, Dediff. Liposarcoma	10

Table 6: Summary of Clinical Pharmacokinetic (PK) and Receptor Occupancy (RO) Data for OR-502 (NCT06090266 - Dose Escalation)

Parameter	Finding	Source(s)
PK - Dose Proportionality	Roughly dose-proportional (100-1600 mg)	11
PK - Terminal Half-life (t½)	Approx. 8-16 days (Mono: 7.6-15.9 days; Combo: 8.4-12.4 days, dose-dependent)	11
PK - Impact of Cemiplimab	No apparent effect on OR-502 PK	11
RO - Peripheral Myeloid Cells	Near-complete RO on classical monocytes & neutrophils at doses $\geq$200 mg (e.g., 96% monocytes, 89% neutrophils at 200mg mono C2D1)	11
RO - Impact of Cemiplimab	No apparent effect on OR-502 RO	11
Dosing Regimen Supported by PK/RO	800 mg IV Q3W for expansion cohorts	10

6. Discussion and Future Perspectives

The development of OR-502 as a LILRB2-targeting monoclonal antibody represents a promising advancement in the field of cancer immunotherapy. The available preclinical and emerging clinical data provide a foundation for its continued investigation, particularly highlighting its potential to modulate the tumor microenvironment by targeting myeloid cell-mediated immunosuppression.

6.1. Interpretation of Current Findings

The current body of evidence suggests that OR-502 possesses a differentiated profile. Preclinically, it has demonstrated superior functional activity compared to benchmark anti-LILRB2 antibodies across a range of in vitro assays, including more effective ligand blockade, cytokine modulation (favoring a Th1 response), and enhancement of T-cell effector functions.[4] This superiority extended to in vivo humanized mouse models, where OR-502 monotherapy led to significant tumor regression.[4] These preclinical attributes, potentially stemming from its distinct binding epitope on LILRB2 and the functional consequences of its IgG1 isotype (including Fc$\gamma$R co-engagement), lend credence to the "best-in-class" potential often emphasized by its developers.[3]

The initial data from the Phase 1 portion of the NCT06090266 trial appear to support this potential. OR-502 has exhibited an "excellent safety profile," being well-tolerated up to 1600 mg Q3W without dose-limiting toxicities.[15] This favorable safety is a significant asset, particularly for an immunomodulatory agent. Coupled with this safety, "compelling early efficacy signals" have been observed with OR-502 monotherapy in heavily pretreated patients with various advanced solid tumors, including durable partial responses and a disease control rate of 65% in an initial cohort of 17 evaluable patients.[10] The observed clinical activity in diverse tumor types such as mucosal melanoma, NSCLC, and dedifferentiated liposarcoma suggests that its mechanism of action may have broad applicability.

Furthermore, the clinical pharmacokinetic and receptor occupancy data are encouraging. OR-502 displays predictable, dose-proportional PK with a half-life of 8-16 days, suitable for Q3W dosing. Near-complete peripheral LILRB2 receptor occupancy on myeloid cells is achieved at doses of 200 mg and above, well within the tolerated dose range, indicating robust target engagement.[11] The lack of PK or RO interference when combined with cemiplimab simplifies the development of combination strategies. Collectively, these findings suggest that the proposed mechanism of LILRB2 blockade and myeloid cell reprogramming is translating from preclinical models into tangible clinical activity and target engagement in humans.

6.2. Positioning of OR-502 in the Immuno-Oncology Landscape

LILRB2 inhibitors, including OR-502, are part of an emerging class of myeloid checkpoint inhibitors that aim to overcome limitations of current T-cell-centric immunotherapies.[9] A significant challenge in oncology is primary or acquired resistance to PD-1/PD-L1 inhibitors. The composition and functional state of myeloid cells within the TME are recognized as critical determinants of this resistance. Immunosuppressive TAMs, for instance, can directly inhibit T-cell function and promote an environment that is non-permissive for effective anti-tumor immunity.

OR-502, by targeting LILRB2 on these myeloid cells, offers a rational strategy to dismantle this layer of immunosuppression.[3] This could potentially re-sensitize tumors to T-cell checkpoint inhibitors or enhance their efficacy when used in combination from earlier lines of therapy. The planned expansion cohorts in PD-(L)1 pretreated melanoma and NSCLC within the NCT06090266 trial are designed to directly test this hypothesis.[10] Success in these populations would position OR-502 as a valuable therapeutic option for patients with high unmet medical needs. The broader landscape of LILRB2/ILT4 inhibitors includes other agents in clinical development, such as AstraZeneca's AZD2796 [18], making the differentiation of OR-502 through its unique binding characteristics, IgG1 effector function, and clinical performance particularly important.

6.3. Future Clinical Development and Potential Indications

The OR502-101 (NCT06090266) study is actively progressing. With the dose-escalation phase complete, the trial is now focused on expansion cohorts. Mini-expansion cohorts are currently recruiting patients with PD-(L)1 pretreated cutaneous melanoma (OR-502 monotherapy) and NSCLC (OR-502 in combination with cemiplimab) at the selected 800 mg Q3W dose.[10] Further expansion cohorts are planned for patients with PROC and CSCC.[6]

A key output of the ongoing study will be the determination of the RP2D for OR-502, which will inform the design of subsequent, potentially registrational, trials. Integral to this effort is the evaluation of biomarkers.[3] While specific biomarkers are not detailed in the provided materials, identifying predictive biomarkers—such as LILRB2 expression levels on myeloid cells, specific TME myeloid signatures, or HLA ligand expression patterns—will be crucial for optimizing patient selection in future studies. A robust biomarker strategy could significantly enhance the probability of success by enriching for patient populations most likely to derive benefit from LILRB2 blockade, a common and critical approach in modern precision oncology.

6.4. Regulatory Considerations

OncoResponse has designed the OR502-101 study with an awareness of the evolving regulatory landscape, particularly the FDA's Project Optimus initiative. This initiative encourages more thorough dose exploration and optimization earlier in clinical development to identify the minimal effective dose that maintains efficacy while minimizing toxicity.[10] The adaptive elements incorporated into the trial design, allowing for adjustments based on emerging data and FDA interactions, reflect a proactive approach to meeting these regulatory expectations. This may streamline later stages of development and facilitate regulatory discussions. Currently, no specific regulatory designations such as Fast Track, Orphan Drug, or Breakthrough Therapy for OR-502 have been mentioned in the provided documentation.[19]

7. Conclusion

OR-502 is an investigational humanized IgG1 monoclonal antibody targeting the inhibitory myeloid checkpoint receptor LILRB2. Developed by OncoResponse, it embodies a strategy of harnessing insights from "Elite Cancer Responders." Its proposed mechanism involves blocking LILRB2-ligand interactions, thereby reprogramming immunosuppressive myeloid cells in the TME to enhance both innate and adaptive anti-tumor immunity. The IgG1 isotype may further contribute to myeloid cell activation via Fc$\gamma$R engagement.

Preclinical data for OR-502 are robust, demonstrating high-affinity binding, superior functional activity in modulating cytokine production and T-cell responses compared to benchmark antibodies, and significant monotherapy anti-tumor efficacy, including tumor regression in humanized mouse models. These findings provide a strong rationale for its clinical development.

The ongoing Phase 1/2 clinical trial (NCT06090266) has yielded encouraging early results. OR-502 has shown an excellent safety profile, with no DLTs observed up to 1600 mg Q3W. Preliminary efficacy signals in heavily pretreated patients with advanced solid tumors include durable partial responses and a notable disease control rate with monotherapy. Clinical PK and RO data support an 800 mg Q3W dosing regimen for expansion cohorts, demonstrating dose-proportional PK and near-complete target engagement.

OR-502 holds promise as a novel immunotherapeutic agent, both as a monotherapy and, critically, in combination with T-cell checkpoint inhibitors like cemiplimab. Its potential to overcome resistance to existing immunotherapies by targeting a distinct arm of the immune system—myeloid cell-mediated suppression—positions it as an important candidate in the evolving immuno-oncology landscape. The continued progress of the NCT06090266 trial, particularly in the expansion cohorts focusing on specific tumor types and immunotherapy-refractory populations, will be crucial in further defining the therapeutic role and "best-in-class" potential of OR-502.

8. References

[1]

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