Comprehensive Report on GLB-002: An Investigational IKZF1/3 Molecular Glue Degrader for Non-Hodgkin Lymphoma

1. Executive Summary

GLB-002 is an orally administered, next-generation, selective molecular glue degrader targeting the lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3).[1] Developed by GluBio Therapeutics Inc., a clinical-stage biotechnology company specializing in Targeted Protein Degradation (TPD), GLB-002 represents a novel therapeutic approach for hematological malignancies.[1] The drug functions by inducing the ubiquitination and subsequent proteasomal degradation of IKZF1 and IKZF3, proteins known to be critical for the survival and proliferation of certain lymphoma and myeloma cells.

Currently, GLB-002 is undergoing evaluation in a Phase 1 clinical trial (NCT06219356; GLB-002-01). This first-in-human (FIH), open-label, multicenter study is actively recruiting patients in China with various subtypes of relapsed or refractory Non-Hodgkin Lymphoma (R/R NHL). The trial employs a dose escalation and expansion design to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of GLB-002 monotherapy.

Initial results from the first dose cohort (Cohort 1) have been reported as positive.[1] GLB-002 demonstrated excellent PK, PD, safety, and tolerability profiles at the initial dose level. Crucially, the expected extent of IKZF1/3 degradation was achieved, confirming target engagement in humans.[1] Following successful review by the Safety Review Committee, the trial has progressed to dose escalation, with the second cohort now open for enrollment.[1]

By targeting IKZF1 and IKZF3—transcription factors previously considered challenging to inhibit with conventional small molecules—GLB-002 leverages the TPD mechanism to potentially address significant unmet medical needs in patients with R/R NHL. As the second molecular glue degrader from GluBio Therapeutics to enter clinical trials, GLB-002 underscores the company's focus and capabilities in the rapidly evolving field of TPD.[1] Further clinical data will be essential to fully define its therapeutic potential within the competitive landscape of NHL treatments.

2. Introduction

2.1. Overview of Non-Hodgkin Lymphoma (NHL)

Non-Hodgkin Lymphoma (NHL) represents a heterogeneous group of hematological cancers originating from lymphocytes, the cells of the immune system. NHL encompasses numerous subtypes, distinguished by their cellular origin (B-cell, T-cell, or NK-cell), morphology, immunophenotype, genetic features, and clinical behavior. Common B-cell NHL subtypes include Diffuse Large B-Cell Lymphoma (DLBCL), which is the most frequent aggressive form, and Follicular Lymphoma (FL), the most common indolent (slow-growing) form. Other significant subtypes include Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL), and Small Lymphocytic Lymphoma (SLL)/Chronic Lymphocytic Leukemia (CLL).

Standard first-line treatment for many NHL subtypes, particularly B-cell lymphomas, often involves chemoimmunotherapy regimens, such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). While these approaches can lead to remission and potential cure in a substantial proportion of patients, particularly those with aggressive lymphomas like DLBCL, a significant number face challenges. Many patients with indolent lymphomas like FL eventually relapse, and a considerable fraction of patients across various NHL subtypes either do not respond adequately to initial treatment (refractory disease) or experience disease recurrence after an initial response (relapsed disease). Managing relapsed or refractory (R/R) NHL presents a major clinical challenge, underscoring the critical unmet medical need for novel, effective, and well-tolerated therapeutic strategies.

2.2. Targeted Protein Degradation (TPD) as a Therapeutic Strategy

Targeted Protein Degradation (TPD) has emerged as a transformative drug discovery paradigm, offering a distinct mechanism of action compared to traditional occupancy-based inhibition.[1] Instead of merely blocking a protein's function, TPD utilizes the cell's own natural protein disposal machinery—primarily the ubiquitin-proteasome system (UPS)—to selectively eliminate specific disease-causing proteins. This process involves small molecules designed to bring a target protein into close proximity with an E3 ubiquitin ligase, leading to the target protein being tagged with ubiquitin molecules and subsequently recognized and destroyed by the proteasome.

TPD offers several potential advantages over conventional inhibitors. Perhaps most significantly, it enables the targeting of proteins previously considered "undruggable" due to the lack of well-defined enzymatic active sites or binding pockets suitable for traditional inhibitors. This includes challenging targets like transcription factors and scaffolding proteins. Furthermore, TPD can exhibit catalytic activity, meaning a single degrader molecule can mediate the destruction of multiple target protein molecules before potentially being recycled, potentially leading to more profound and durable target suppression at lower drug concentrations. By physically removing the target protein, TPD eliminates all its functions, including both enzymatic and non-enzymatic scaffolding roles, which may overcome resistance mechanisms associated with inhibitors that only block one aspect of protein function.

2.3. Molecular Glue Degraders

Molecular glue degraders represent a specific class within the TPD field.[2] These are typically small molecules, often with molecular weights below 500 Da, that function by inducing or stabilizing the interaction between a target protein (often referred to as a "neosubstrate") and a component of an E3 ubiquitin ligase complex, such as a substrate receptor. This drug-induced proximity facilitates the formation of a ternary complex (E3 ligase–glue–target protein). Once this complex forms, the E3 ligase ubiquitinates the target protein, marking it for degradation by the proteasome.

A prominent example of molecular glue action involves the Cereblon (CRBN) protein, which acts as a substrate receptor for the CUL4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase complex. The discovery that immunomodulatory drugs (IMiDs) like thalidomide, lenalidomide, and pomalidomide function as molecular glues binding to CRBN and inducing the degradation of specific neosubstrates (notably the transcription factors IKZF1 and IKZF3) revolutionized the understanding of their mechanism and spurred intense interest in developing novel molecular glues.

Molecular glues differ from another major class of TPD agents, Proteolysis Targeting Chimeras (PROTACs). PROTACs are larger, heterobifunctional molecules designed with two distinct binding moieties connected by a linker: one binds the target protein, and the other binds an E3 ligase. While PROTAC design can be more modular, molecular glues are generally smaller and more compact. This smaller size may confer advantages in terms of physicochemical properties, such as improved cell permeability, metabolic stability, and potential for oral bioavailability, making them attractive drug candidates.

2.4. Introduction to GLB-002

GLB-002 is an investigational therapeutic agent developed by GluBio Therapeutics Inc. that embodies the principles of molecular glue-mediated TPD.[1] It is specifically characterized as a next-generation, selective molecular glue degrader targeting the transcription factors IKZF1 (Ikaros) and IKZF3 (Aiolos).[1] GLB-002 is currently being evaluated in early-phase clinical trials for the treatment of patients with R/R NHL, aiming to leverage the targeted degradation of these key lymphoid factors to achieve therapeutic benefit.[1]

3. GLB-002: Drug Profile and Scientific Rationale

3.1. Drug Identity

GLB-002 is identified by its primary designation and several synonyms. It is classified as a degradable molecular glue, specifically targeting IKZF1 and IKZF3 for elimination via the cellular protein degradation machinery.[1] The development is spearheaded by GluBio Therapeutics Inc. and its subsidiary, Hangzhou GluBio Pharmaceutical Co., Ltd..[1] Consistent with its classification as a molecular glue and its intended oral route of administration in clinical trials, GLB-002 is inferred to be a small molecule compound. The small molecule nature is a defining characteristic of molecular glues and is fundamental to their potential for oral delivery and favorable pharmacokinetic profiles compared to larger therapeutic modalities like biologics or even PROTACs.

Table 1: GLB-002 Drug Profile Summary

Feature	Detail	Source(s)
Name	GLB-002
Synonyms	GLB 002, GLB A062 B
Drug Type	Selective Molecular Glue Degrader	1
Target(s)	IKZF1 (Ikaros), IKZF3 (Aiolos)	1
Mechanism of Action	Induced degradation of IKZF1/IKZF3 (likely via CRBN E3 ligase)	1
Developer	GluBio Therapeutics Inc. / Hangzhou GluBio Pharmaceutical Co., Ltd.	1
Highest Phase	Phase 1	3
Key Indication	Relapsed/Refractory Non-Hodgkin Lymphoma (R/R NHL)	3

3.2. Developer: GluBio Therapeutics Inc.

GluBio Therapeutics Inc. is a clinical-stage biotechnology company founded in March 2021, with a dedicated focus on discovering and developing innovative TPD therapies for unmet medical needs.[1] The company maintains headquarters in San Diego, California, and conducts research operations in both the United States and Shanghai, China.[1]

Shortly after its inception, GluBio secured substantial financial backing, raising nearly US$90 million from a syndicate of top-tier life sciences investors, including Hillhouse Ventures, Qiming Venture Partners, Eli Lilly Asia Ventures, Kaitai Capital, and Legend Capital.[1] This significant early-stage funding reflects considerable investor confidence in the company's specialized TPD platform, experienced team (noted as having extensive experience in developing molecular glue and PROTAC drugs [2]), and the potential of its emerging pipeline. Such financial resources are crucial for advancing novel drug candidates through the capital-intensive process of clinical development.

GluBio has established a comprehensive TPD drug discovery engine, encompassing proprietary platforms for multi-dimensional protein degradation screening, target identification and validation, rational design of molecular glues, and a proprietary library of molecular glue compounds.[1] The company leverages these capabilities, including computational chemistry and high-throughput screening assays, to pursue both "First-in-class" and "Best-in-class" small molecule TPD drugs, including molecular glues and heterobifunctional degraders.[1]

GLB-002 is positioned within a focused pipeline of TPD assets.[3] It is the company's second molecular glue degrader to reach clinical trials, following GLB-001, which targets CK1α and is in Phase 1 development for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS).[1] The rapid progression of two distinct molecular glue candidates into Phase 1 within approximately three years of the company's founding highlights the productivity of GluBio's R&D platform and efficient execution, as noted by the company's leadership. The broader pipeline includes earlier-stage programs targeting WEE1 (bifunctional degrader for solid tumors), WIZ (molecular glue for sickle cell disease and β-Thalassemia), an undisclosed target for Renal Cell Carcinoma (molecular glue), and multiple discovery-stage molecular glue programs for solid tumors.[2] This portfolio demonstrates a strategic commitment to TPD, particularly molecular glues, across diverse therapeutic areas and targets, positioning GLB-002 as a key asset within a systematic drug discovery effort rather than an isolated project.

Table 2: GluBio Therapeutics Pipeline Overview (as of 2025)

Program	Target	Modality	Indication	Stage
GLB-001	CK1α	Molecular Glue	AML & MDS	Phase 1
GLB-002	IKZF1/3	Molecular Glue	MM & NHL	Phase 1
GLB-003	WEE1	Bifunctional Degrader	Solid Tumors	Lead Optimization
GLB-004	Undisclosed	Molecular Glue	Renal Cell Carcinoma	Lead Optimization
GLB-005	WIZ	Molecular Glue	SCD & β-Thalassemia	Lead Optimization
Multiple Programs	Undisclosed	Molecular Glue	Solid Tumors	Discovery

Source: [3]

3.3. Mechanism of Action (MoA)

GLB-002 functions as a molecular glue degrader, inducing the selective elimination of its target proteins, IKZF1 and IKZF3.[1] The fundamental mechanism involves GLB-002 mediating the formation of a ternary complex between the target proteins and an E3 ubiquitin ligase. This proximity allows the E3 ligase to tag IKZF1 and IKZF3 with ubiquitin chains, signaling them for destruction by the cellular proteasome.

While the specific E3 ligase utilized by GLB-002 is not explicitly named in the provided materials, the overwhelming precedent for IKZF1/3 degraders points towards the involvement of Cereblon (CRBN), the substrate receptor component of the CRL4CRBN E3 ligase complex. Virtually all well-characterized IKZF1/3 degraders, from the original IMiDs to newer clinical candidates like iberdomide (CC-220), CFT7455, and SP-3164, operate through CRBN recruitment. Given that GLB-002 is described as a "next-generation" IKZF1/3 degrader, it most likely builds upon this established CRBN-mediated mechanism. Assuming CRBN involvement is important, as factors influencing CRBN expression or function (e.g., mutations) could potentially impact GLB-002 activity, similar to observations with IMiDs.

A key characteristic emphasized for GLB-002 is its selectivity for IKZF1/3.[1] This suggests that the molecule has been rationally designed, likely leveraging GluBio's platform capabilities [2], to preferentially induce the degradation of Ikaros and Aiolos over other potential CRBN neosubstrates. Older IMiDs are known to degrade other proteins besides IKZF1/3, contributing to their broader activity profile and potentially some toxicities. Newer molecular glues, including candidates targeting GSPT1 (e.g., CC-90009, Mezigdomide) or CK1α (e.g., GLB-001, SJ3149, INNO-220), demonstrate that specific chemical modifications can tune neosubstrate specificity.[3] The "next-generation" label for GLB-002 likely refers, at least in part, to this enhanced selectivity, which could translate into an improved therapeutic window by concentrating the degradation effect on the primary targets relevant to NHL pathogenesis while minimizing potential off-target liabilities associated with degrading other proteins.

Crucially, pharmacodynamic data from the first cohort of the Phase 1 clinical trial provided initial validation of GLB-002's mechanism in humans.[1] The study reported that GLB-002 achieved the "expected extent of IKZF1/3 degradation" in patients treated at the first dose level.[1] This confirmation of target engagement is a critical early milestone for any TPD therapeutic, providing evidence that the drug reaches its intended targets and successfully initiates the degradation process at clinically achievable exposures. This finding supports the proposed MoA and provides confidence for continued dose escalation aimed at achieving therapeutically relevant levels of IKZF1/3 degradation.

3.4. Target Rationale: IKZF1 (Ikaros) and IKZF3 (Aiolos) in NHL

The selection of IKZF1 (Ikaros) and IKZF3 (Aiolos) as targets for GLB-002 is grounded in their established roles in lymphocyte biology and malignancy, particularly in B-cell cancers.

IKZF1 and IKZF3 belong to the Ikaros family of zinc-finger transcription factors. They play essential roles in the development, differentiation, and proliferation of various lymphocyte lineages, including B cells, T cells, and NK cells. Their functions involve regulating the expression of numerous genes critical for lymphocyte identity and function, often through mechanisms involving chromatin remodeling.

The therapeutic relevance of targeting IKZF1 and IKZF3 was firmly established through studies elucidating the mechanism of IMiDs (thalidomide, lenalidomide, pomalidomide). These drugs exert potent anti-myeloma activity largely by acting as molecular glues that induce the CRBN-mediated degradation of IKZF1 and IKZF3. These transcription factors are considered essential dependency factors for the survival of malignant plasma cells in Multiple Myeloma (MM).

The rationale extends to various subtypes of NHL:

• Diffuse Large B-Cell Lymphoma (DLBCL): Preclinical studies with the IKZF1/3 degrader CC-122 demonstrated apoptosis in DLBCL cell lines and tumor growth inhibition in xenograft models, linked to the degradation of IKZF1/3 and subsequent modulation of interferon-regulated genes. Lenalidomide, which degrades IKZF1/3, has shown clinical activity in DLBCL, particularly the activated B-cell like (ABC) subtype where it inhibits the key survival factor IRF4, a downstream target of IKZF1/3 degradation. Furthermore, genetic screens identified IKZF1 loss as a sensitizing factor for EZH2 inhibition in DLBCL, supporting combination strategies involving IKZF1/3 degradation.
• Follicular Lymphoma (FL): Lenalidomide is an established treatment option for R/R FL, acting partly through IKZF1/3 degradation. Preclinical data with SP-3164, another IKZF1/3 degrader, showed single-agent activity and enhanced efficacy when combined with standard FL agents like tazemetostat (an EZH2 inhibitor) or venetoclax (a BCL2 inhibitor) in FL xenograft models.
• Mantle Cell Lymphoma (MCL): Lenalidomide is used clinically in R/R MCL, especially for patients unsuitable for intensive chemotherapy. Its mechanism in MCL involves the degradation of IKZF1/3, leading to derepression of IL-2 expression and subsequent activation of anti-tumor immune responses mediated by T cells and NK cells.
• Marginal Zone Lymphoma (MZL): Lenalidomide also has clinical activity in R/R MZL, with IKZF1/3 degradation considered part of its mechanism.

A key aspect of the rationale for targeting IKZF1 and IKZF3 with degraders is that these transcription factors lack conventional druggable binding pockets, making them largely intractable to traditional small molecule inhibitors. TPD approaches, particularly molecular glues, circumvent this limitation by targeting them for destruction rather than inhibition.

Beyond direct cytotoxic effects on lymphoma cells, the degradation of IKZF1/3 has significant immunomodulatory consequences. By removing these repressors, degraders can enhance T-cell and NK-cell activation and function, partly through increased IL-2 production. There is also evidence suggesting effects on regulatory T cells (Tregs). This dual mechanism—direct tumor cell killing combined with immune system activation—may contribute to more potent and durable anti-lymphoma responses. GLB-002, as an IKZF1/3 degrader, could potentially harness both these direct and indirect anti-tumor effects. The pharmacodynamic assessments in the ongoing Phase 1 trial likely include monitoring of immune cell populations and activation markers to evaluate these immunomodulatory effects.

4. Preclinical Development

Specific preclinical data detailing the characterization and evaluation of GLB-002 are limited in the publicly available sources provided. However, contextual information from the developer and related compounds allows for inferences regarding the likely scope of preclinical work performed.

GluBio Therapeutics' pipeline information indicates that GLB-002 targets both Multiple Myeloma (MM) and Non-Hodgkin Lymphoma (NHL).[3] This suggests that the preclinical program likely involved studies in cell lines and potentially animal models relevant to both disease areas. Independent databases, such as AdisInsight, also corroborate preclinical activity being investigated in DLBCL and MM prior to the initiation of the Phase 1 trial in January 2024.

While direct GLB-002 data is scarce, results reported for other investigational IKZF1/3 molecular glue degraders provide a relevant benchmark for the types of preclinical activities expected:

• In vitro cytotoxicity: Compounds like PPM-100 demonstrated cytotoxic effects against various cancer cell lines, including the OCI-Ly3 NHL cell line. SP-3164 also showed activity in NHL models. CC-122 induced apoptosis in DLBCL cell lines. It is highly probable that GLB-002 was similarly tested across a panel of NHL cell lines representing different subtypes (e.g., DLBCL, FL, MCL) to establish its anti-proliferative activity.
• Target Degradation: Confirmation of selective and potent degradation of IKZF1 and IKZF3 proteins in relevant cell lines would be a critical preclinical step, often measured by techniques like Western blotting or quantitative proteomics.
• Mechanism Validation: Demonstrating that the observed effects are dependent on the molecular glue mechanism (e.g., requiring CRBN) would typically be assessed using genetic knockout/knockdown or chemical inhibition approaches.
• Downstream Effects: Investigating downstream consequences of IKZF1/3 degradation, such as effects on cell cycle (observed for PPM-100), apoptosis pathways, interferon signaling (observed for CC-122), or key oncogenes like c-MYC (degradation observed for PPM-100), would help elucidate the biological impact.
• Immunomodulation: Assessing effects on immune cells, such as T-cell activation (e.g., IL-2 production) or modulation of pro-inflammatory cytokines, is relevant given the known immunomodulatory roles of IKZF1/3 degradation.
• In vivo Efficacy: Evaluation in animal models, typically xenografts using human NHL cell lines implanted into immunodeficient mice, is standard practice to assess anti-tumor activity, tolerability, and pharmacodynamic effects (target degradation in tumors) in a living system. Studies might explore single-agent activity as well as combinations with other relevant therapies (e.g., SP-3164 combined with tazemetostat or venetoclax in an FL model).

Although specific data for GLB-002 are not provided in the snippets, the successful progression to a FIH clinical trial implies that a comprehensive preclinical package demonstrating activity, target engagement, and an acceptable preliminary safety profile was generated and submitted to regulatory authorities (analogous to the IND process described in). The positive initial clinical results reported for Cohort 1 further support the predictive value of the underlying preclinical work.[1]

5. Clinical Development: Phase 1 Trial (NCT06219356 / GLB-002-01)

5.1. Overview

GLB-002 is currently being investigated in a Phase 1 clinical trial identified by the identifiers NCT06219356 and GLB-002-01. A corresponding registration exists in the Chinese Clinical Trial Registry under CTR20233717. The study is formally titled "A Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of GLB-002 in Patients With Relapsed or Refractory Non-Hodgkin Lymphomas (R/R NHL)".

This trial represents the first time GLB-002 has been administered to humans (First-in-Human, FIH).[1] It is designed as an open-label, multicenter study conducted exclusively at sites within China.[1] The trial is sponsored by Hangzhou GluBio Pharmaceutical Co., Ltd., the China-based entity associated with GluBio Therapeutics Inc.. As of the latest updates (August 2024), the trial status is active and recruiting participants. The primary purpose of the study is therapeutic investigation.

Table 3: Key Clinical Trial Details (NCT06219356 / GLB-002-01)

Parameter	Detail	Source(s)
Identifiers	NCT06219356, GLB-002-01, CTR20233717
Title	A Phase 1 Study to Evaluate... GLB-002 in Patients With Relapsed or Refractory Non-Hodgkin Lymphomas
Phase	1
Status	Active, Recruiting (as of Aug 2024)
Sponsor	Hangzhou GluBio Pharmaceutical Co., Ltd.
Design	FIH, Open-label, Multicenter (China), Dose Escalation (1a) & Expansion (1b), Sequential Assignment
Primary Objectives	Evaluate Safety, Tolerability; Determine MTD/RED
Key Secondary Objectives	Characterize PK, Assess PD (IKZF1/3 degradation), Evaluate Preliminary Efficacy
Estimated Enrollment	110 participants
Start Date	January 11, 2024
Est. Completion Date	February 28, 2027
Location(s)	Multiple sites in China

5.2. Design and Objectives

The trial follows a standard two-part design common for FIH oncology studies: Part 1a (Dose Escalation) and Part 1b (Dose Expansion).[1] Participants are assigned sequentially to dose cohorts.

Part 1a (Dose Escalation): The primary goal of this phase is to determine the safety and tolerability profile of GLB-002 administered orally across ascending dose levels in patients with various R/R NHL subtypes. Key objectives include identifying dose-limiting toxicities (DLTs) and establishing the maximum tolerated dose (MTD) and/or identifying appropriate doses for further study (Recommended Expansion Doses, RED). Secondary objectives in this part include evaluating the PK profile, assessing PD markers (including the extent of IKZF1/3 degradation), and gathering preliminary signals of anti-tumor activity.

Part 1b (Dose Expansion): Once suitable dose(s) and schedules are identified in Part 1a, the study transitions to Part 1b. This phase involves enrolling distinct cohorts of patients with specific R/R NHL subtypes to further evaluate the tolerability of the selected regimen(s) and, importantly, to assess preliminary efficacy within these defined populations. The goal is to determine if the observed efficacy signals warrant further clinical development in these specific indications. The planned expansion cohorts are:

• Cohort 1: R/R Follicular Lymphoma (FL), Grades 1, 2, or 3a.
• Cohort 2: R/R Diffuse Large B-cell Lymphoma (DLBCL) and R/R FL Grade 3b.
• Cohort 3: Other R/R NHL subtypes, explicitly mentioning Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL), and Small Lymphocytic Lymphoma (SLL) as possibilities, but not limited to these.

The inclusion of expansion cohorts targeting specific NHL subtypes (FL, DLBCL, MCL, MZL, SLL) is a significant aspect of the trial design. It allows for early assessment of GLB-002's activity across a spectrum of NHL histologies where IKZF1/3 degradation is considered a relevant therapeutic strategy based on preclinical data and the known activity of related compounds like lenalidomide. This structured approach aims to efficiently gather preliminary efficacy data to guide subsequent, potentially registrational, clinical trials.

5.3. Patient Population

The trial aims to enroll approximately 110 participants. Eligibility is restricted to adult patients (≥ 18 years old) with a confirmed diagnosis of R/R NHL who have exhausted or are ineligible for standard therapeutic options. The study requires patients to have an acceptable performance status (ECOG 0, 1, or 2), a life expectancy exceeding 3 months, and adequate major organ function. For the dose expansion phase (Part 1b), patients must have measurable disease according to standard criteria.

Exclusion criteria are designed to ensure patient safety and minimize confounding factors. Patients are excluded if they have received recent anticancer therapies (including chemotherapy, targeted therapy, immunotherapy, CAR-T cell therapy) or participated in other investigational drug studies within specified washout periods. Recent autologous or allogeneic stem cell transplantation is also exclusionary. Other key exclusions include known active CNS involvement by the lymphoma, active GVHD requiring systemic immunosuppression, significant cardiac dysfunction (including prolonged QTc interval), active viral hepatitis (HBV/HCV), and conditions that might significantly alter the drug's absorption, distribution, metabolism, or excretion (ADME).

Notably, the protocol excludes concomitant use of medications or supplements known to be strong or moderate inhibitors or inducers of the cytochrome P450 enzyme CYP3A4/5 and/or the drug transporter P-glycoprotein (P-gp) within a defined period before starting GLB-002. This specific exclusion strongly suggests that GLB-002's metabolism and/or transport likely involves these common pathways, highlighting a potential area for drug-drug interactions that needs careful management as development progresses.

Table 4: Key Eligibility Criteria Summary (NCT06219356)

Category	Key Criteria	Source(s)
Inclusion	Diagnosis: Histologically confirmed R/R NHL (WHO 2016 / IWCLL 2018) failed Standard of Care (SOC) or lack effective options
	Age: ≥ 18 years
	Performance Status: ECOG 0, 1, or 2
	Life Expectancy: > 3 months
	Organ Function: Adequate hematologic, liver, kidney, coagulation function
	Measurable Disease: Required for Phase 1b
Exclusion	Prior Therapy Washouts: Recent chemo, targeted, immuno, CAR-T, SCT
	CNS Disease: Known active CNS lymphoma/leukemia involvement
	GVHD/Immunosuppression: Active GVHD requiring systemic therapy; Corticosteroids >10mg/day prednisone equiv.
	Cardiac: QTc interval > 470 ms; Clinically significant cardiac disease
	Infections: Active HBV or HCV
	ADME Issues: Conditions affecting drug absorption, distribution, metabolism, excretion
	Concomitant Medications: Strong/moderate CYP3A4/5 or P-gp inhibitors/inducers within washout period
	Other: Cognitive impairment limiting compliance; Investigator judgment of unsuitability

5.4. Treatment Plan

Participants in the trial receive GLB-002 administered orally. The specific dose levels being evaluated in the dose escalation phase (Part 1a) are not detailed in the provided materials. Dosing schedules are also not specified but will be determined during Part 1a and confirmed for the expansion cohorts in Part 1b. Treatment continues as per protocol unless criteria for discontinuation (e.g., disease progression, unacceptable toxicity) are met.

5.5. Study Logistics

The trial officially commenced on January 11, 2024, and has an estimated study completion date of February 28, 2027. All currently listed study sites are located in China. Participating centers include several prominent cancer hospitals: Beijing Cancer Hospital (identified as the lead site under Prof. Yuqin Song), Sun Yat-Sen University Cancer Center (Guangzhou), Henan Cancer Hospital (Zhengzhou), Jiangxi Cancer Hospital (Nanchang), Fudan University Shanghai Cancer Center (Shanghai), Tianjin Medical University Cancer Institute and Hospital (Tianjin), and The First Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou).

The decision to conduct this FIH trial exclusively in China is noteworthy. While GluBio Therapeutics has operations in both the US and China, initiating the first clinical study solely in China may reflect various strategic factors, such as access to experienced clinical investigators like Prof. Song, potentially faster patient recruitment for R/R NHL, alignment with the company's Shanghai research base, or specific regulatory considerations within China. While NHL biology is generally similar across populations, results generated solely from a Chinese patient cohort may require confirmation in broader, global studies to ensure generalizability, particularly regarding potential ethnic variations in drug metabolism or response. The primary contact listed for the trial is Jing Liu, MD, associated with GluBio Therapeutics.

5.6. Preliminary Results (Cohort 1)

As of February 23, 2024, GluBio Therapeutics announced the successful completion of dosing and the DLT observation period for the first dose cohort (Cohort 1) of the GLB-002-01 study.[1] This milestone was achieved rapidly, within two months of the study's initiation.

The initial findings from Cohort 1 were reported as highly positive.[1] GLB-002 was described as exhibiting "excellent" pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability at this first dose level.[1] A key finding was the confirmation of target engagement: the drug achieved the "expected extent of IKZF1/3 degradation" in treated patients.[1]

Following these encouraging results, a Safety Review Committee (SRC) meeting was successfully completed, endorsing the progression of the study.[1] Consequently, the second dose cohort (Cohort 2) was opened for patient recruitment, allowing the trial to evaluate the safety and activity of GLB-002 at the next planned dose level.[1]

These preliminary data represent a significant positive step for the GLB-002 program. Demonstrating good tolerability, favorable PK characteristics, and clear evidence of on-target PD activity (IKZF1/3 degradation) in the very first human cohort provides strong validation for the drug's mechanism and potential. It de-risks the program considerably compared to entering the clinic with unknowns regarding human safety or target engagement. The rapid completion of the first cohort also suggests efficient trial management and execution by GluBio and the participating clinical sites. Based on these initial PK/PD readouts, GluBio leadership expressed optimism that GLB-002 holds promise as a future novel treatment option for patients with R/R NHL.[1]

6. Therapeutic Landscape and Future Directions

6.1. Potential Positioning in R/R NHL

Should GLB-002 continue to demonstrate favorable efficacy and safety in ongoing and future clinical trials, it could emerge as a valuable therapeutic option for patients with R/R NHL across various subtypes. As an oral agent leveraging the novel TPD mechanism, it could potentially fill gaps left by existing therapies, including conventional chemoimmunotherapy and potentially other targeted agents like Bruton's tyrosine kinase inhibitors (BTKi) or phosphoinositide 3-kinase inhibitors (PI3Ki), depending on the patient's prior treatment history and specific NHL subtype.

The precise positioning of GLB-002 within the increasingly complex NHL treatment landscape will depend heavily on data generated from the Phase 1b expansion cohorts and subsequent Phase 2/3 studies. Key factors will include its efficacy (overall response rate, duration of response, progression-free survival) and safety profile compared to other established and emerging therapies, such as CAR-T cell therapies, bispecific antibodies, antibody-drug conjugates, and other novel targeted agents. Its activity profile across different NHL histologies (DLBCL, FL, MCL, MZL, etc.) as assessed in the expansion cohorts will be crucial for defining its specific niche(s). The convenience of oral administration could be an advantage over infused therapies if efficacy and safety are comparable.

6.2. Comparison with Other IKZF1/3 Degraders

GLB-002 enters a field where the concept of IKZF1/3 degradation is clinically validated but also increasingly competitive.

• Established IMiDs: Lenalidomide (Revlimid) and pomalidomide (Pomalyst) are widely used, particularly in MM and certain NHL settings. However, their activity extends beyond IKZF1/3 degradation, and they are associated with specific toxicity profiles (e.g., myelosuppression, thromboembolism, neuropathy). "Next-generation" degraders like GLB-002 aim to improve upon IMiDs by potentially offering enhanced potency, greater selectivity specifically for IKZF1/3 (potentially reducing off-target effects), or activity in IMiD-resistant settings.
• Clinical Competitors: Several other potent, selective IKZF1/3 molecular glue degraders are also in clinical development, representing direct competitors. Iberdomide (CC-220, BMS/Celgene) is in Phase 2/3 trials for MM and has been studied in NHL and Systemic Lupus Erythematosus. CFT7455 (C4 Therapeutics) is another potent IKZF1/3 degrader in Phase 1/2 trials for MM and R/R NHL (NCT04756726). GLB-002, currently in Phase 1, will need to demonstrate a compelling clinical profile relative to these agents, which are further along in development for some indications. Differentiation could come from superior efficacy in specific NHL subtypes, an improved safety profile (perhaps linked to its specific selectivity profile), different PK/PD characteristics, or activity in populations resistant to other therapies. Head-to-head comparative data are not available.
• Alternative Degradation Strategies: The field also includes degraders with broader or different target profiles. For instance, Mezigdomide (CC-92480, BMS/Celgene) primarily targets GSPT1 but also degrades IKZF1/3. BTX-1188 (Bullseye Therapeutics) is a dual degrader targeting both GSPT1 and IKZF1/3, currently in Phase 1 for AML and solid tumors. Compounds like SJ7095 aim to degrade both CK1α and IKZF1/3. These represent alternative TPD approaches within the hematological malignancy space.

The development landscape underscores the need for GLB-002 to clearly define its advantages. Its success will likely hinge on demonstrating a differentiated profile—whether through superior efficacy, better tolerability, activity in specific resistant populations, or a unique spectrum of activity across NHL subtypes—compared to both established IMiDs and contemporary IKZF1/3 degraders like iberdomide and CFT7455.

Table 5: Overview of Selected IKZF1/3-Targeting Degraders

Drug Name	Developer	Target(s)	Modality	Highest Phase	Key Indication(s)	Source(s)
GLB-002	GluBio Therapeutics	IKZF1/3	Selective Molecular Glue	Phase 1	R/R NHL, MM	3
Iberdomide	BMS / Celgene	IKZF1/3	Molecular Glue (CELMoD)	Phase 2/3	MM, NHL, SLE
CFT7455	C4 Therapeutics	IKZF1/3	Molecular Glue	Phase 1/2	MM, R/R NHL
SP-3164	Salarius Pharma	IKZF1/3	Molecular Glue (S-avadomide)	Preclinical (NHL)	NHL
PPM-100	Protheragen	IKZF1/3	Molecular Glue	Preclinical	Blood Cancers, Solid Tumors
Mezigdomide	BMS / Celgene	GSPT1, IKZF1/3	Molecular Glue (CELMoD)	Phase 2	RRMM
BTX-1188	Bullseye Therapeutics	GSPT1, IKZF1/3	Dual Molecular Glue	Phase 1	AML, Solid Tumors
Lenalidomide	BMS / Celgene	IKZF1/3, others	Molecular Glue (IMiD)	Approved	MM, MDS, NHL (FL, MZL, MCL)
Pomalidomide	BMS / Celgene	IKZF1/3, others	Molecular Glue (IMiD)	Approved	MM, Kaposi Sarcoma

Note: CELMoD = Cereblon E3 Ligase Modulating Drug; IMiD = Immunomodulatory Imide Drug.

6.3. Future Development Pathways

The immediate future for GLB-002 involves the completion of the ongoing Phase 1 trial (NCT06219356). This includes completing dose escalation to establish the MTD/RED and fully enrolling and evaluating the dose expansion cohorts in specific R/R NHL subtypes (DLBCL, FL, MCL, MZL, SLL). Data from these expansion cohorts will be critical for identifying the most promising indications for further development.

Based on the Phase 1b results, GluBio Therapeutics will likely initiate Phase 2 studies designed to more definitively assess efficacy and further characterize safety in selected R/R NHL populations demonstrating encouraging responses [Implied standard drug development path]. Given the preclinical rationale and pipeline listing [3], exploration of GLB-002 in Multiple Myeloma is also a potential future direction, possibly following initial NHL development or in parallel if resources permit.

Combination strategies are highly probable in future development. Based on preclinical rationale and clinical practice with related agents, potential combination partners in NHL could include anti-CD20 monoclonal antibodies (like rituximab), BCL2 inhibitors (like venetoclax, synergistic with SP-3164 in FL models), EZH2 inhibitors (like tazemetostat, synergistic with lenalidomide in DLBCL models and SP-3164 in FL models), or potentially immune checkpoint inhibitors, given the immunomodulatory effects of IKZF1/3 degradation.

Finally, to achieve broader regulatory approval beyond China (e.g., from the US FDA or European EMA), GluBio will likely need to conduct clinical trials including patients from diverse geographical regions and ethnic backgrounds. Expansion to global clinical trial sites would be a necessary step for widespread adoption if the drug proves successful.

7. Conclusion

GLB-002 represents a rationally designed, next-generation therapeutic candidate operating through the targeted protein degradation mechanism. As an orally available, selective molecular glue degrader of the transcription factors IKZF1 and IKZF3, it targets key drivers of lymphocyte development and malignancy implicated across various subtypes of Non-Hodgkin Lymphoma. Developed by GluBio Therapeutics, a company focused on TPD, GLB-002 leverages a validated mechanism—IKZF1/3 degradation—while potentially offering improvements in selectivity compared to earlier-generation immunomodulatory agents.

The scientific rationale for targeting IKZF1/3 in NHL is robust, supported by the clinical success of IMiDs in related malignancies and preclinical evidence implicating these factors in NHL cell survival and immune modulation. The ongoing Phase 1 clinical trial (NCT06219356) in China is appropriately designed to assess the safety, tolerability, PK, PD, and preliminary efficacy of GLB-002 in patients with R/R NHL.

The preliminary results from the first dose cohort are notably encouraging, demonstrating good initial safety and tolerability, favorable pharmacokinetics, and, critically, evidence of successful target engagement through IKZF1/3 degradation in patients. This early success provides a strong foundation for continued clinical investigation and dose escalation.

While still in early-stage development, GLB-002 holds significant promise as a potential new treatment option for patients with R/R NHL, a population with substantial unmet medical needs. Its future success will depend on generating compelling efficacy and safety data from the ongoing Phase 1 expansion cohorts and subsequent larger trials. Differentiation from other emerging IKZF1/3 degraders and defining its optimal place within the evolving NHL treatment landscape, potentially including combination regimens, will be key challenges. Nonetheless, based on its mechanism, target rationale, and positive initial clinical signals, GLB-002 warrants continued attention as a potentially impactful TPD therapeutic.

8. References

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1. Successful Completion of Dose Escalation at the First Dose Level in ..., accessed May 2, 2025, https://www.glubiotx.com/news/204eeb1fadd89cc35818ed25be4c97bb
2. GluBio Therapeutics, accessed May 2, 2025, https://www.glubiotx.com/sciences#platform
3. GluBio Therapeutics, accessed May 2, 2025, https://www.glubiotx.com/sciences#pipeline