HX009: A Comprehensive Clinical and Scientific Monograph on a First-in-Class Anti-PD-1/CD47 Bispecific Antibody

Executive Summary

Overview

HX009 is a first-in-class, recombinant humanized bispecific antibody (BsAb) fusion protein under clinical investigation for the treatment of advanced malignancies. It is engineered to concurrently target two distinct and complementary immune checkpoints: the programmed cell death protein 1 (PD-1) on T-cells, a cornerstone of the adaptive immune system, and the cell surface antigen CD47 on tumor cells, a key regulator of the innate immune system's phagocytic response.[1] This dual-targeting strategy is designed to orchestrate a multi-pronged anti-tumor immune attack by simultaneously reactivating exhausted T-cells and disabling the primary "don't eat me" signal used by cancer cells to evade macrophage-mediated destruction.

Core Scientific Innovation

The central innovation of HX009 lies in its rational molecular design, which aims to optimize the therapeutic index by overcoming the principal limitation of prior CD47-targeted therapies: on-target, off-tumor hematological toxicity. The molecule is engineered with a high-affinity binding domain for PD-1 and a deliberately weakened binding affinity for CD47.[3] This design leverages the localization of PD-1-expressing T-cells within the tumor microenvironment (TME) to selectively "hone" the therapeutic agent to the site of the tumor. This localized concentration is intended to facilitate effective engagement with CD47 on adjacent cancer cells while minimizing systemic binding to CD47 expressed on healthy hematopoietic cells, thereby mitigating the risk of severe anemia and thrombocytopenia that has challenged the development of other agents in this class.[3]

Clinical Development Synopsis

HX009 is undergoing a global clinical development program sponsored by Hanx Biopharmaceuticals, with trials conducted in Australia, China, and the United States.[5] The program is evaluating the agent's potential across a spectrum of advanced solid tumors and hematologic malignancies. Early-phase clinical data have demonstrated promising signals of antitumor activity. Objective responses have been observed in heavily pre-treated patients with solid tumors, including gallbladder adenocarcinoma, triple-negative breast cancer, metastatic squamous cell carcinoma of the head and neck, and advanced melanoma that has progressed after prior immune checkpoint inhibitor (CPI) therapy.[5] In hematologic malignancies, HX009 has shown activity in relapsed/refractory (R/R) lymphomas, including in patients with Epstein-Barr virus-positive (EBV+) non-Hodgkin lymphoma (NHL) and a patient with documented resistance to prior PD-1 therapy.[3]

Safety and Tolerability

Across multiple Phase 1 and Phase 1b studies, HX009 has demonstrated a manageable and well-tolerated safety profile. Dose-escalation studies have proceeded up to 15 mg/kg without the identification of a maximum tolerated dose (MTD) or dose-limiting toxicities (DLTs).[3] The majority of treatment-related adverse events (TRAEs) have been Grade 1 or 2 in severity. While hematological toxicities, particularly anemia, have been observed, they have been generally manageable and appear less severe than those associated with first-generation CD47 inhibitors, providing early clinical validation for the drug's engineered safety profile.[3]

Expert Outlook

HX009 represents a sophisticated, second-generation approach to dual immune checkpoint blockade. Its rational design directly addresses a known, class-wide toxicity issue for CD47-targeting agents, potentially creating a superior therapeutic window. The preliminary clinical data are encouraging, particularly the signals of efficacy in immunotherapy-resistant tumors, which points to a clear and significant unmet medical need. While the current evidence is derived from early-phase, single-arm studies and requires validation in larger, randomized trials, HX009 stands out as a scientifically compelling asset. Its future success will be contingent on confirming the durability of responses and demonstrating a clear benefit over existing standards of care in well-defined patient populations.

Scientific Rationale and Mechanism of Action

Introduction to HX009

HX009 is a recombinant humanized bispecific antibody fusion protein developed for oncologic indications.[1] It is identified by several synonyms and code names, including anti-PD-1/CD47 infusion protein HX009, anti-PD1/CD47 bi-specific antibody fusion protein HX009, HX 009, and HX-009.[1] The therapeutic is formulated for intravenous administration, with clinical protocols typically utilizing an every-2-week (Q2W) dosing schedule.[3]

The Dual Immune Checkpoint Blockade Strategy: A Synergistic Approach

The therapeutic hypothesis underpinning HX009 is that the simultaneous blockade of two distinct immune regulatory pathways—one governing the adaptive immune response and the other the innate immune response—will elicit a more comprehensive and potent antitumor effect than targeting either pathway in isolation.[1]

Targeting the Adaptive Immune System (PD-1)

The first target of HX009 is the Programmed cell death protein 1 (PD-1; also known as PDCD1 or CD279), an inhibitory receptor expressed on the surface of activated T lymphocytes.[1] In the TME, tumor cells and other stromal cells can express the ligands for PD-1, namely PD-L1 and PD-L2. The engagement of PD-1 by its ligands triggers downstream signaling pathways that functionally "exhaust" T-cells, suppressing their proliferation, cytokine production, and cytotoxic activity. This PD-1/PD-L1 axis is a primary mechanism through which tumors evade destruction by the adaptive immune system.[1] By binding to PD-1 on T-cells, HX009 physically obstructs the interaction with PD-L1 and PD-L2. This blockade releases the "brakes" on T-cell function, restoring the capacity of effector T-cells and cytotoxic T-lymphocytes (CTLs) to recognize and eliminate cancer cells.[1] This mechanism of action is shared with the well-established class of approved immune checkpoint inhibitors (ICIs) that have revolutionized cancer therapy.[6]

Targeting the Innate Immune System (CD47)

The second target is CD47, also known as integrin-associated protein (IAP), a ubiquitously expressed transmembrane protein that functions as a crucial self-recognition marker.[1] CD47 serves as the ligand for the signal regulatory protein alpha (SIRPα), an inhibitory receptor expressed on myeloid cells, most notably macrophages and dendritic cells (DCs). The interaction between CD47 on a target cell and SIRPα on a macrophage delivers a powerful inhibitory "don't eat me" signal, which prevents phagocytosis.[1] While CD47 is present on most healthy cells, many types of cancer cells overexpress it as a mechanism to protect themselves from being engulfed and cleared by the innate immune system.[1]

HX009 is designed to bind to CD47 on the surface of tumor cells. This binding blocks the CD47/SIRPα interaction, thereby abrogating the inhibitory signal. The removal of this "don't eat me" signal allows pro-phagocytic signals, such as the interaction between calreticulin on the tumor cell surface and LRP on the macrophage, to dominate. This shift in signaling balance activates macrophages and promotes the specific phagocytosis of tumor cells.[1]

Synergistic Action

The dual-targeting nature of HX009 is intended to create a powerful synergy. The PD-1 blockade component unleashes the T-cell-mediated adaptive immune response, leading to direct tumor cell killing. Simultaneously, the CD47 blockade component removes the protective shield from tumor cells, making them vulnerable to clearance by the macrophage-driven innate immune response. Furthermore, the phagocytosis of tumor cells by macrophages and DCs facilitates the processing and presentation of tumor-associated antigens (TAAs), which can further prime and expand the T-cell response, creating a self-amplifying cycle of antitumor immunity.[1]

Molecular Engineering for an Optimized Therapeutic Index

A defining feature of HX009 is its sophisticated molecular engineering, which was conceived as a direct solution to a well-documented, class-wide challenge for CD47-targeting therapies. The widespread expression of CD47 on healthy cells, particularly red blood cells (RBCs) and platelets, means that potent, high-affinity CD47 blockade can lead to significant on-target, off-tumor toxicities, primarily anemia and thrombocytopenia, due to macrophage-mediated clearance of these healthy cells.[1] This has been a major impediment to the development of first-generation anti-CD47 agents.

HX009 was rationally designed to circumvent this issue through a differential affinity approach.[3] The antibody possesses a high-affinity binding domain for PD-1 but a deliberately engineered,

weakened binding affinity for CD47.[3] The logic behind this design is to use the PD-1 interaction as a targeting mechanism. PD-1 is not widely expressed systemically but is upregulated on T-cells that have infiltrated the TME.[1] Consequently, HX009 is expected to preferentially accumulate in the TME by binding to these PD-1-positive tumor-infiltrating lymphocytes (TILs). This selective "honing" to the tumor site increases the local concentration of HX009, enabling its lower-affinity CD47 binding domain to effectively engage CD47 on nearby tumor cells. In contrast, in the systemic circulation, the concentration of HX009 is lower, and its weakened affinity for CD47 is insufficient to cause significant binding to RBCs and platelets. This design aims to maximize on-target, on-tumor activity while minimizing the systemic hematological toxicities that have plagued its predecessors, thereby creating a potentially superior therapeutic window.[3]

Preclinical studies also suggest an additional, potentially unforeseen benefit of this bispecific architecture. Data from reporter assays indicate that HX009 may induce superior T-cell activation compared to a conventional PD-1 monoclonal antibody.[10] This enhanced activation appears to result from a "cis-binding" phenomenon. When the high-affinity PD-1 arm of HX009 binds to a T-cell, it anchors the molecule to the cell surface. This localization increases the effective concentration of the CD47-binding domains in the immediate vicinity of the T-cell membrane, enhancing the avidity (collective binding strength) for CD47, which is also expressed on T-cells. This engagement may provide an additional activating or co-stimulatory signal, suggesting that the bispecific format could be inherently more potent at stimulating T-cells than a simple combination of two separate antibodies.[10]

Preclinical Evidence and Validation

The advancement of HX009 into clinical trials was supported by a robust and methodically executed preclinical program. This program utilized a cascade of increasingly sophisticated in vitro and in vivo models to validate the drug's mechanism of action, demonstrate its antitumor efficacy, and establish a preliminary safety profile. This rigorous approach, conducted in collaboration with the contract research organization Crown Bioscience, was instrumental in building the compelling data package that supported successful Investigational New Drug (IND) applications.[15]

In Vitro and In Vivo Antitumor Activity

Initial preclinical studies confirmed that HX009 effectively inhibited tumor growth in a variety of mouse xenograft models, providing the foundational proof-of-concept for its antineoplastic activity.[5] The evaluation was then extended to more clinically relevant models. In hematologic malignancies, HX009 demonstrated potent anti-lymphoma activity in both cell-derived xenograft (CDX) models, using Raji B-lymphoma and Karpas-299 T-lymphoma cell lines, and in custom-developed patient-derived xenograft (PDX) models, which better reflect the heterogeneity of human disease.[15]

Further studies explored the potential of HX009 in acute myeloid leukemia (AML). Testing on three AML PDX models revealed significant anti-AML activity.[12] Importantly, the degree of antitumor effect in these models was found to correlate with the expression levels of CD47 on the leukemic cells, suggesting that CD47 expression could serve as a potential predictive biomarker for patient selection in future clinical trials.[12]

Evidence of Superiority over Monotherapy

A critical component of the preclinical validation was to demonstrate that the dual-targeting bispecific format of HX009 was superior to targeting either PD-1 or CD47 alone. This was conclusively shown using a highly advanced, genetically engineered mouse model (HuGEMM™).[15] This model involved quadruple knock-in of the human genes for SIRPα, CD47, PD-1, and PD-L1 into mice, creating an environment where the human-specific drug could be tested in the context of a fully intact, autologous murine immune system. In an A20-hCD47 mouse B-lymphoma model established in these HuGEMM™ mice, HX009 exhibited significantly superior anti-lymphoma efficacy compared to treatment with either a PD-1 monoclonal antibody or a CD47-blocking agent (SIRPα-Fc) alone.[15] This result provided the strongest preclinical evidence supporting the hypothesis of synergistic action and the superiority of the bispecific approach.

Non-Human Primate Toxicology Studies

To establish a safe starting dose for human trials, repeat-dose toxicology studies were conducted in Cynomolgus monkeys. These studies are essential for evaluating the potential on-target and off-target toxicities of a novel biologic in a species with high genetic homology to humans. The results of these studies established that the highest non-severely toxic dose of HX009 was 15 mg/kg.[5] This key safety data point informed the design of the first-in-human clinical trial, allowing for the selection of a safe starting dose and a rational dose-escalation scheme.

Clinical Development Program

Program Overview

HX009 is being developed by Hanx Biopharmaceutical Co., Ltd., a global biopharmaceutical company also known by associated names such as Hangzhou Hanx Biopharmaceuticals, Ltd., Waterstone Hanxbio, and Hans-Itai.[7] The clinical development program is global in scope, with key studies being conducted in Australia, China, and the United States, targeting a range of both solid tumors and hematologic malignancies.[5] The comprehensive clinical program is summarized in Table 1.

Trial Identifier	Phase	Primary Indication(s)	Key Regions	Status
NCT04097769	Phase 1	Advanced Solid Malignancies	Australia	Completed
NCT05731752	Phase 1b/2	Advanced Solid Tumors (incl. Melanoma)	Australia, China	Ongoing
NCT05189093	Phase 1/2	Relapsed/Refractory Lymphoma	China, United States	Ongoing
NCT04886271	Phase 2	Advanced Solid Tumors	China	Ongoing
N/A	Phase 2	Biliary Tract Cancer (Combination Therapy)	China	Approved to Start

Table 1: Summary of Key HX009 Clinical Trials [3]

Clinical Evaluation in Advanced Solid Tumors

First-in-Human Dose Escalation (NCT04097769)

The clinical journey for HX009 began with a first-in-human, open-label, Phase 1 dose-escalation study conducted at three sites in Australia.[5] The study employed a standard 3+3 design to evaluate the safety, tolerability, and preliminary efficacy of HX009 as a single agent. The drug was administered via intravenous infusion every two weeks across seven dose levels, ranging from 0.1 mg/kg to 7.5 mg/kg.[5]

The study enrolled 21 patients with a diverse range of heavily pre-treated advanced solid malignancies, who had received a median of three prior lines of anti-cancer therapy. Enrolled tumor types included colorectal cancer, squamous cell carcinoma, endometrial cancer, breast cancer, malignant mesothelioma, gallbladder cancer, pancreatic cancer, glioblastoma, ovarian cancer, and gastroesophageal junction adenocarcinoma.[5]

The primary outcomes demonstrated that HX009 was well-tolerated across all dose levels up to 7.5 mg/kg. Crucially, no dose-limiting toxicities (DLTs) were observed, and a maximum tolerated dose (MTD) was not reached.[5] The majority of TRAEs were Grade 1 or 2, with the most common being nausea, rash, vomiting, and decreased appetite. Only one treatment-related serious adverse event (SAE) of pneumonitis was reported. Notably, only one case of Grade 2 anemia was observed, and there were no instances of treatment-related thrombocytopenia, providing early human evidence supporting the drug's engineered safety profile.[5]

Among the 18 patients evaluable for efficacy, promising signals of antitumor activity were observed. Three patients achieved a confirmed partial response (PR), corresponding to an objective response rate (ORR) of 16.7%. These responses occurred in patients with gallbladder adenocarcinoma (at the 1 mg/kg dose level), triple-negative breast cancer (5 mg/kg), and metastatic squamous cell carcinoma of the head and neck (5 mg/kg). An additional six patients (33.3%) achieved stable disease (SD) as their best overall response.[5] The key findings are summarized in Table 2.

Parameter	Result
Dose Levels Tested	0.1 mg/kg to 7.5 mg/kg
Number of Patients (N)	21
Most Common TRAEs (Grade 1-2)	Nausea, Rash, Vomiting, Decreased Appetite
Grade ≥3 TRAEs	Pneumonitis (1 patient, 4.8%)
Hematologic TRAEs	Anemia Grade 2 (1 patient, 4.8%); Thrombocytopenia (0%)
Dose-Limiting Toxicities (DLTs)	0
Objective Response Rate (ORR)	16.7% (3/18 evaluable patients)
Disease Control Rate (DCR)	50.0% (3 PR + 6 SD)

Table 2: Key Safety and Efficacy Results from the Phase 1 Study in Advanced Malignancies (NCT04097769) [5]

Phase 1b Study in Advanced Melanoma (NCT05731752)

Building on the initial findings, a Phase 1b dose-expansion study was initiated to further investigate HX009 monotherapy at the recommended Phase 2 dose (RP2D) of 10 mg/kg Q2W.[8] A key cohort in this multicenter, open-label study (Cohort B) was designed specifically to evaluate HX009 in patients with advanced melanoma who had progressed on or after prior therapy with immune checkpoint inhibitors (CPIs). This patient population represents a significant and growing unmet medical need, as resistance to standard PD-1/PD-L1 blockade is a major clinical challenge.

As of a data cutoff of November 15, 2024, 19 patients had been treated in Cohort B. This was a heavily pre-treated population, with a median of 1.0 prior lines of therapy (range 1-6), and included 18 patients who had failed prior CPIs.[8] The safety profile in this cohort was consistent with previous findings and considered manageable. The most common TRAEs (≥20%) were anemia (26.3%), increased γ-glutamyl transferase (GGT) (21.1%), and rash (21.1%). Three patients (15.8%) experienced Grade 3 or higher TRAEs, which included one case each of anemia, hypokalemia, and hypophysitis, the latter being a known immune-related adverse event (irAE) associated with PD-1 blockade.[8]

The efficacy results in this highly refractory population were particularly noteworthy. Among 17 efficacy-evaluable patients, the ORR was 17.6% (3 patients achieved a PR). The disease control rate (DCR), which includes patients with stable disease, was 29.4% (3 PRs plus 2 patients with prolonged SD lasting more than 8 months with tumor shrinkage). The durability of these responses was also encouraging, with two of the three responding patients remaining in PR for over 250 days and continuing on treatment at the time of the data cutoff.[8] These results provide a compelling, albeit preliminary, signal that HX009's dual mechanism of action can overcome resistance to prior PD-1 inhibitor therapy. Key results are summarized in Table 3.

Parameter	Result
Number of Patients (N)	19 (in post-CPI cohort)
Median Prior Lines of Therapy	1.0 (range 1-6)
Most Common TRAEs (≥20%)	Anemia (26.3%), GGT Increased (21.1%), Rash (21.1%)
Grade ≥3 TRAEs	15.8% (3 patients)
Objective Response Rate (ORR)	17.6% (3/17 evaluable patients)
Disease Control Rate (DCR)	29.4% (5/17 evaluable patients)
Durability Highlight	2 of 3 PRs ongoing >250 days

Table 3: Key Safety and Efficacy Results from the Phase 1b Study in Post-CPI Advanced Melanoma (NCT05731752) [8]

Clinical Evaluation in Hematologic Malignancies

Phase I/II Study in Relapsed/Refractory Lymphoma (NCT05189093)

To evaluate its potential in hematologic cancers, a multi-center, open-label, single-arm Phase I/II study of HX009 was initiated in patients with R/R lymphoma.[3] The study includes a completed dose-escalation phase (Phase Ia) and an ongoing dose-expansion phase (Phase Ib).[3]

The Phase Ia portion successfully established the safety of escalating doses up to 15 mg/kg, with no DLTs being observed.[3] The most common AEs in this phase were primarily Grade 1-2 hematological events, including anemia (42.9%), decreased white blood cell count (42.9%), and decreased lymphocyte and platelet counts (28.6%).[3]

The ongoing Phase Ib portion is exploring the efficacy of HX009 at a dose of 10 mg/kg Q2W across four parallel cohorts of patients with different lymphoma subtypes: diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphoma (PTCL), follicular lymphoma (FL) or marginal zone lymphoma (MZL), and Epstein-Barr virus-positive non-Hodgkin lymphoma (EBV+ NHL).[3]

EBV+ Non-Hodgkin Lymphoma Cohort Analysis

Preliminary results have been reported from the EBV+ NHL cohort, providing an early look at the drug's activity in this specific population.[3] As of May 7, 2024, 14 patients with R/R EBV+ NHL had been treated. The study protocol allowed for the inclusion of patients who had received prior PD-(L)1 therapy, making this another setting in which to test the drug's ability to overcome immunotherapy resistance.[3]

The safety profile was manageable, with no treatment-related deaths. The most frequent TRAEs (≥20%) were fever (35.7%), decreased lymphocyte and platelet counts (28.6%), and anemia, decreased neutrophil count, and decreased white blood cell count (21.4%). Grade 3 or higher TRAEs (≥10%) were all hematologic, including decreased neutrophils, white blood cells, lymphocytes, and anemia (all occurring in 14.3% of patients). Treatment-related SAEs included anemia (14.3%) and infectious pneumonia (7.1%).[3]

Among 13 efficacy-evaluable patients, 3 (23.1%) achieved a PR. These responses were observed in patients with particularly challenging and aggressive disease subtypes: one with a PD-1 resistant DLBCL, one with PTCL, and one with a DLBCL that had transformed into a PTCL. The response in a patient with documented resistance to a prior PD-1 inhibitor is a powerful clinical proof-of-concept for the added benefit of the dual-targeting mechanism. In addition to the objective responses, four other patients (30.8%) achieved stable disease.[3] These findings are summarized in Table 4.

Parameter	Result
Number of Patients (N)	14
Most Common TRAEs (≥20%)	Fever (35.7%), Cytopenias (21.4% - 28.6%)
Grade ≥3 TRAEs (≥10%)	Cytopenias (14.3%)
Treatment-Related SAEs	Anemia (14.3%), Infectious Pneumonia (7.1%)
Objective Response Rate (ORR)	23.1% (3/13 evaluable patients)
Disease Control Rate (DCR)	53.8% (3 PR + 4 SD)

Table 4: Key Safety and Efficacy Results from the Phase Ib EBV+ NHL Cohort (NCT05189093) [3]

Emerging Indications and Combination Strategies

The clinical development strategy for HX009 demonstrates a nimble, evidence-driven approach. Early signals of activity are being rapidly translated into dedicated expansion cohorts and new trials.

Biliary Tract Cancer (BTC)

The observation of a confirmed PR in a patient with gallbladder adenocarcinoma during the initial Phase 1 study provided a strong rationale to pursue biliary tract cancer as a key indication.[5] This single data point from a broad "all-comers" trial was sufficient to justify a more focused investigation. This led to a strategic pivot: on September 5, 2024, HanX Biopharmaceuticals announced that it had received approval from China's National Medical Products Administration (NMPA) to initiate a Phase 2 clinical trial of HX009 specifically for BTC.[7] Significantly, this new trial will evaluate HX009 in

combination with another therapy, not as a monotherapy. This reflects a strategic recognition that combination regimens are likely to be the most effective path forward for immuno-oncology agents in many solid tumors.

Integrated Safety and Tolerability Profile

A comprehensive analysis of safety data aggregated across the reported Phase 1 and 1b clinical trials reveals a consistent and manageable tolerability profile for HX009, even at doses up to 15 mg/kg.[3] This favorable profile provides the first clinical validation for the rational design hypothesis, suggesting that the molecular engineering to mitigate toxicity has been successful.

Common Adverse Events

Across studies in both solid tumors and hematologic malignancies, the most frequently reported TRAEs have been predominantly low-grade (Grade 1-2). These include constitutional symptoms such as nausea, decreased appetite, and fever, as well as dermatologic events like rash.[3] These events are generally consistent with the known side effect profiles of other immunotherapies and are typically managed with supportive care.

Hematological Toxicity Analysis

Given the known risks of CD47-targeting agents, hematological toxicity has been a key area of focus. The clinical data for HX009 indicate a notable mitigation of these risks. While anemia is the most common hematologic AE, with Grade 1-2 events reported in 26.3% of melanoma patients and 42.9% of lymphoma patients in a Phase Ia cohort, the rates of severe anemia appear manageable.[3] For instance, Grade 3 or higher anemia was reported in 14.3% of patients in the EBV+ NHL cohort.[3] Critically, in the first-in-human solid tumor study, which included 21 patients, there were no reported cases of treatment-related thrombocytopenia, a significant concern with first-generation CD47 inhibitors.[5] This favorable hematologic profile, especially the lack of severe thrombocytopenia, strongly supports the conclusion that the weakened CD47 binding affinity has successfully reduced systemic toxicity on circulating blood cells.

Serious Adverse Events (SAEs) and Immune-Related AEs (irAEs)

A small number of treatment-related SAEs have been reported. These include cases of pneumonitis, infectious pneumonia, and hypophysitis.[3] These events are well-characterized irAEs known to be associated with PD-1/PD-L1 blockade. Their occurrence suggests that the safety profile of HX009 is, in part, reflective of its PD-1 inhibitor component and can be monitored and managed using established clinical guidelines for ICIs.

Dose-Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD)

A key finding from the dose-escalation phases of the clinical program is that HX009 has been well-tolerated at all doses tested. No DLTs have been observed, and an MTD has not been reached in studies that have escalated the dose up to 15 mg/kg.[3] This indicates a wide therapeutic window and provides flexibility for selecting an optimal, biologically active dose for Phase 2 and 3 studies without being constrained by toxicity.

Pharmacokinetics and Immunogenicity

As is standard for the development of novel biologic therapies, the clinical program for HX009 includes a comprehensive plan for the characterization of its pharmacokinetic (PK) and immunogenicity profiles.[5]

Pharmacokinetic Parameters

In all clinical studies, serial blood samples are collected from patients to conduct a thorough analysis of the drug's PK properties. The planned analyses aim to determine a full panel of standard PK parameters, including peak plasma concentration (Cmax​), time to peak concentration (Tmax​), trough concentration (Cmin​), area under the concentration-time curve (AUC), terminal half-life (t1/2​), clearance (CLss​/F), and volume of distribution (Vz​/F).[5] The results from these analyses, which are critical for understanding drug exposure and confirming the appropriateness of the dosing schedule, have been noted in study publications as forthcoming and will be presented at future scientific meetings.[5]

Immunogenicity

The potential for a biologic drug to elicit an immune response in patients is a critical safety consideration. The development of anti-drug antibodies (ADAs) can impact a drug's efficacy, safety, and pharmacokinetics. Accordingly, the HX009 clinical program includes systematic monitoring for the development of ADAs in all treated patients. For patients who test positive for ADAs, further analysis is conducted to determine the presence of neutralizing antibodies (NAbs), which are ADAs that can directly inhibit the drug's biological activity.[5] This systematic assessment is essential for fully characterizing the safety and long-term efficacy profile of HX009.

Regulatory and Development Status

Developer

HX009 was discovered and is being developed by Hanx Biopharmaceutical Co., Ltd., a global biopharmaceutical company based in Wuhan and Hangzhou, China.[6] The company is also referred to in various sources as Hangzhou Hanx Biopharmaceuticals, Ltd., Waterstone Hanxbio, and Hans-Itai.[7]

Global Regulatory Milestones

The development of HX009 has progressed through key regulatory milestones in several major jurisdictions, reflecting a global clinical strategy.

• United States (Food and Drug Administration - FDA): On May 22, 2023, Hanx Biopharmaceuticals announced that it had received Investigational New Drug (IND) approval from the FDA. This approval authorized the company to initiate a Phase IB/II clinical study in the United States to evaluate HX009 in patients with relapsed/refractory lymphoma who have failed standard therapies.[6]
• China (National Medical Products Administration - NMPA): Clinical development is active in China, including Phase 1 and 2 studies in solid tumors and lymphomas.[3] A significant recent milestone was achieved on September 5, 2024, when the NMPA granted IND approval for a Phase 2 trial of HX009 administered as part of a combination therapy regimen for patients with biliary tract cancer.[7]
• Australia (Therapeutic Goods Administration - TGA): Australia served as the initial site for the clinical evaluation of HX009. The first-in-human dose-escalation study (NCT04097769) and the subsequent Phase 1b study in advanced melanoma (NCT05731752) were both conducted at Australian clinical sites.[5] This indicates early and successful engagement with the TGA to secure the necessary approvals to conduct these trials. There is no information available regarding a marketing application submission to the TGA.
• Europe (European Medicines Agency - EMA): The provided research materials contain no information regarding clinical trial applications, scientific advice, or marketing authorization submissions to the EMA.[22]

Current Status

Based on the available information, HX009 is currently in Phase 2 clinical development for solid tumors and in Phase 1/2 development for various lymphoma indications.[7]

Expert Analysis and Future Outlook

Synthesis of Evidence: A Promising Next-Generation Immunotherapy

HX009 emerges from the available data as a well-conceived and rationally designed bispecific antibody that represents a significant evolution in the field of immuno-oncology. The core strength of the program lies in its foundational science: the molecular engineering to confer weakened CD47 binding as a direct strategy to mitigate the class-wide hematological toxicities of CD47 inhibitors. The early clinical safety data, characterized by a manageable AE profile and the absence of an MTD up to high dose levels, provides compelling validation for this design hypothesis. Furthermore, the dual-targeting mechanism, which engages both innate and adaptive immunity, is supported by robust preclinical data demonstrating superiority over monotherapy and, more importantly, by early clinical signals of activity in patient populations that are resistant to current standards of care, including PD-1 inhibitors.

Positioning in the Therapeutic Landscape

The potential clinical utility of HX009 can be assessed within the context of its primary target indications, each of which presents a distinct set of challenges and opportunities.

• Relapsed/Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL): The treatment paradigm for R/R DLBCL has been revolutionized by the approval of CD19-directed CAR T-cell therapies (axicabtagene ciloleucel, lisocabtagene maraleucel), which are now the standard of care for patients with primary refractory disease or early relapse.[27] For patients in later lines or those ineligible for CAR-T, options include CD20xCD3 bispecific antibodies (glofitamab, epcoritamab) and antibody-drug conjugates (polatuzumab vedotin).[27] A significant unmet need persists for patients who are ineligible for, or who relapse after, CAR-T therapy. HX009 could be positioned in this post-CAR-T setting. The observed partial response in a patient with documented PD-1 resistant DLBCL is a particularly powerful piece of data, suggesting that HX009 may offer a mechanism of action capable of overcoming resistance to both chemotherapy and prior immunotherapy, potentially carving out a unique niche.
• Post-CPI Advanced Melanoma: For patients with advanced melanoma whose disease progresses after treatment with PD-1 inhibitors, therapeutic options are limited and outcomes are poor. The 17.6% ORR observed with HX009 monotherapy in this specific population is clinically meaningful.[8] If these results are replicated and the responses are shown to be durable in larger studies, HX009 could establish a new standard of care as a second- or third-line therapy for this large and growing patient population.
• Biliary Tract Cancer (BTC): The standard of care for first-line advanced BTC has recently been established as gemcitabine-cisplatin plus the PD-L1 inhibitor durvalumab.[32] For second-line treatment, options like FOLFOX offer modest benefit.[33] The early monotherapy PR signal for HX009 in gallbladder cancer was a strong indicator of activity.[5] The strategic decision to advance HX009 into a Phase 2 trial in combination therapy for BTC suggests it is being positioned to either enhance the current first-line standard or to provide a more effective second-line option.[7]

Critical Assessment and Unanswered Questions

Despite the promising profile, it is imperative to acknowledge the limitations of the current data and the critical questions that remain to be answered.

• Data Maturity: All available clinical evidence for HX009 is from early-phase, single-arm studies with small patient cohorts. While these trials are essential for establishing safety and identifying signals of efficacy, the true therapeutic benefit and definitive safety profile can only be ascertained through larger, randomized controlled trials that compare HX009 to an established standard of care.
• Durability of Response: While some durable responses have been reported, such as those lasting over 250 days in melanoma patients, the median duration of response across different indications is not yet established.[8] Long-term follow-up from ongoing and future trials will be critical to determine if the responses induced by HX009 are transient or can lead to long-term disease control, a key determinant of its clinical value.
• Biomarker Strategy: Preclinical data in AML models suggested a correlation between CD47 expression and antitumor activity, pointing to a potential predictive biomarker.[12] However, a validated biomarker for patient selection has not yet been identified or implemented in the clinical trials for solid tumors or lymphomas. The development of a robust biomarker strategy would be invaluable for enriching for patient populations most likely to respond and for optimizing the drug's clinical development path.
• Competitive Landscape: HX009 is entering an intensely competitive and rapidly evolving immuno-oncology landscape. It will face competition not only from established therapies but also from a multitude of other novel agents, including other bispecific antibodies targeting different checkpoint combinations. Its ultimate success will depend on its ability to demonstrate a clearly superior efficacy and/or safety profile in head-to-head comparisons or in well-defined patient populations with high unmet needs.

Concluding Remarks

In conclusion, HX009 is a first-in-class anti-PD-1/CD47 bispecific antibody distinguished by a rational molecular design aimed at enhancing safety and efficacy. The preclinical evidence is robust, and the early clinical data are encouraging, showing a manageable safety profile and promising signals of antitumor activity, most notably in immunotherapy-resistant settings. The program's development has been guided by a clear, data-driven strategy. While significant hurdles remain, and the definitive clinical value of HX009 is contingent upon the results of larger, controlled Phase II and III studies, it stands as a significant and scientifically compelling asset in the pipeline of Hanx Biopharmaceuticals and a noteworthy example of next-generation bispecific antibody engineering.

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