Pulocimab (AK109): A Comprehensive Analysis of a Novel VEGFR2 Inhibitor and its Strategic Role in Overcoming Immunotherapy Resistance

Executive Summary and Strategic Overview

Pulocimab, also known by its development code AK109, is an investigational humanized IgG1 monoclonal antibody meticulously engineered to target and antagonize the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2).[1] Its primary mechanism of action is the inhibition of tumor neoangiogenesis, a process fundamental to the growth and metastasis of solid tumors. By competitively blocking the binding of Vascular Endothelial Growth Factor (VEGF) to VEGFR2, Pulocimab disrupts the critical signaling cascade that promotes the formation of new blood vessels, thereby depriving tumors of essential nutrients and oxygen, which ultimately leads to cancer cell death.[1]

The clinical development program for Pulocimab is strategically focused on addressing one of the most significant challenges in modern oncology: acquired resistance to immune checkpoint inhibitors (immunotherapy, IO). The agent is not being developed as a standalone therapy but as a cornerstone component of novel combination regimens, primarily with cadonilimab, Akeso Biopharma’s first-in-class bispecific antibody targeting both Programmed cell death protein 1 (PD-1) and Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).[4] This combination is predicated on a strong scientific rationale wherein the anti-angiogenic effects of Pulocimab are hypothesized to remodel the tumor microenvironment, making it more permissive to the potent anti-tumor immune response elicited by dual checkpoint blockade.

Promising efficacy signals have emerged from Phase Ib/II clinical trials in two distinct, difficult-to-treat patient populations. In patients with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma who have progressed on first-line immunochemotherapy, the triplet combination of Pulocimab, cadonilimab, and paclitaxel has demonstrated statistically significant improvements in objective response rate (ORR) and progression-free survival (PFS) compared to a control arm, leading to the initiation of a pivotal Phase III trial.[7] Furthermore, in immunotherapy-resistant non-small cell lung cancer (NSCLC), the chemotherapy-free doublet of Pulocimab and cadonilimab has shown a notable extension in median overall survival (mOS), offering a potentially transformative treatment option for patients with limited alternatives.[4]

The safety profile of Pulocimab, both as a single agent and in combination, has been characterized as manageable and is consistent with the known class effects of VEGFR inhibitors. The most frequently observed treatment-related adverse events include proteinuria, hypertension, and hematological toxicities, which are predictable and familiar to oncologists.[8]

Currently, Pulocimab remains an investigational agent without marketing approval in any jurisdiction. However, its development program, particularly the combination with cadonilimab, has received a Breakthrough Therapy Designation from China's National Medical Products Administration (NMPA) for advanced squamous NSCLC.[4] The successful execution of ongoing and planned Phase III registration trials will be critical in determining its future. If validated, Pulocimab is positioned not merely as another anti-angiogenic agent but as a key synergistic component capable of unlocking the full potential of dual checkpoint inhibition and establishing a new standard of care in immunotherapy-resistant solid tumors.

1. Introduction to Pulocimab: A Second-Generation Anti-Angiogenic Agent

1.1. Molecular Profile and Development Rationale

Pulocimab is a precisely engineered biologic therapeutic agent classified as a humanized recombinant monoclonal antibody.[13] Known by its development identifier AK109, it belongs to the Immunoglobulin G1 (IgG1) subclass with a kappa light chain, a common structural framework for therapeutic antibodies that confers stability and effector functions.[1] The molecular design of Pulocimab is highly specific; it is engineered to target and bind with high affinity to the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), a receptor tyrosine kinase also referred to as Kinase Insert Domain Receptor (KDR).[1]

The fundamental scientific rationale for the development of Pulocimab is rooted in the pivotal role of angiogenesis in cancer pathophysiology. Tumors, beyond a certain size, require the formation of new blood vessels—a process known as neoangiogenesis—to sustain their growth, proliferation, and ability to metastasize.[1] The signaling pathway mediated by VEGF and its primary receptor on endothelial cells, VEGFR2, is the most dominant and well-characterized driver of this process. By functioning as a direct antagonist of VEGFR2, Pulocimab is designed to intercept this critical signaling axis. This inhibition of tumor-associated neoangiogenesis is intended to "starve" the tumor, leading to hypoxia and nutrient deprivation, which in turn provokes cancer cell death and inhibits metastatic spread.[1]

While the current development is being spearheaded by Akeso Biopharma, the origins of the antibody's core components trace back to earlier research. The peptide sequences that constitute the variable domains of Pulocimab's heavy and light chains, which are responsible for its specific binding to VEGFR2, were originally claimed in patent WO2003075840A2, filed by Imclone Systems Inc..[1] This indicates that the foundational intellectual property was established well before its incorporation into Akeso's clinical pipeline, a common practice in pharmaceutical development where promising molecules are acquired or licensed for further advancement.

Table 1: Key Characteristics of Pulocimab (AK109)

Characteristic	Description	Source Snippet(s)
Generic Name	Pulocimab	1
Development Code	AK109, AK-109	1
Compound Class	Recombinant Monoclonal Antibody	1
Host/Isotype	Humanized, Human IgG1, kappa	1
Target	VEGFR2 (KDR)	1
Mechanism of Action	VEGFR2 Antagonist, Angiogenesis Inhibitor	2
Developer	Akeso Biopharma / AD Pharmaceuticals	16
Expression System	Chinese Hamster Ovary (CHO) cells	13

1.2. Developer and Manufacturing

The primary developer advancing Pulocimab through clinical trials is Akeso Biopharma (also cited as Akeso, Inc. and Akesobio), a biopharmaceutical company with a stated focus on developing innovative therapies for major diseases, particularly in the fields of cancer and autoimmune disease.[4] Akeso has established a comprehensive, end-to-end drug development infrastructure, highlighted by its Akeso Comprehensive Exploration (ACE) Platform and its proprietary Tetrabody technology for creating bi-specific antibodies.[4] The development of Pulocimab fits within its broader corporate strategy of creating a robust pipeline of over 50 innovative assets, many of which are designed to work synergistically to address complex clinical challenges such as therapeutic resistance.[4]

The manufacturing process for Pulocimab employs standard, industry-accepted methods for producing high-quality monoclonal antibodies for clinical use. It is generated using a recombinant expression system in Chinese Hamster Ovary (CHO) cells, which are widely used for their ability to perform complex post-translational modifications, such as glycosylation, that are critical for the function and stability of human-like antibodies.[13] Following expression, the antibody is isolated and purified from the cell culture medium using Protein A/G affinity chromatography, a highly effective and standard technique for capturing IgG antibodies.[13] The final product is formulated as a liquid solution in phosphate-buffered saline (PBS) at a pH of 7.4, without preservatives, and is stored under controlled temperature conditions to maintain its integrity.[13]

1.3. Addressing Data Discrepancies

A critical assessment of the available information reveals a significant data discrepancy originating from a single source. A commercial product listing from Thermo Fisher Scientific for a recombinant antibody (catalog # MA562669) labeled "Pulocimab" anomalously describes it as an "anti-IL-33 antibody under study for asthma and allergic diseases".[13] This assertion stands in stark contradiction to the entire body of pharmacological, clinical, and corporate data available for the investigational drug Pulocimab (AK109).

Every other high-authority source—including the IUPHAR/BPS Guide to PHARMACOLOGY, the DrugBank database, drug development pipeline trackers like AdisInsight and Synapse, all registered clinical trial protocols (e.g., NCT04547205, NCT04982276, NCT06341335), peer-reviewed publications of clinical trial results, and official press releases from the developer Akeso—definitively and consistently identifies Pulocimab (AK109) as an anti-VEGFR2 monoclonal antibody being developed exclusively for oncological indications.[1]

The discrepancy can be confidently resolved as an error within the commercial product catalog. The Thermo Fisher product is intended for in vitro research applications such as ELISA and flow cytometry, not for human clinical administration.[13] It is not uncommon for such research-grade reagents to have naming or descriptive errors in large commercial catalogs. The complete absence of any mention of Interleukin-33 (IL-33), asthma, or allergic diseases in the extensive clinical development program for AK109 confirms that the IL-33 reference is an outlier and factually incorrect in the context of the therapeutic agent. Therefore, for the purposes of this comprehensive report, Pulocimab is unequivocally defined as an anti-VEGFR2 antibody for the treatment of cancer.

2. Pharmacological Profile: Mechanism of Action and Pharmacokinetics

2.1. Molecular Mechanism of Action

Pulocimab exerts its anti-tumor effects through a precise and well-defined molecular mechanism: the direct antagonism of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2).[2] As a humanized monoclonal antibody, Pulocimab is designed to recognize and bind with high specificity and affinity to an extracellular domain of the VEGFR2 protein expressed on the surface of endothelial cells.[1] This binding is competitive in nature; it physically obstructs the receptor's ligand-binding site, thereby preventing the endogenous ligand, Vascular Endothelial Growth Factor A (VEGF-A), from docking and activating the receptor.[1]

The binding of VEGF-A to VEGFR2 is the rate-limiting step in initiating a potent intracellular signaling cascade that is the primary driver of angiogenesis. This cascade involves receptor dimerization, autophosphorylation of tyrosine residues in the cytoplasmic domain, and the subsequent activation of multiple downstream pathways, including the PLCγ-PKC-MAPK and PI3K-Akt pathways. These pathways collectively orchestrate the proliferation, migration, survival, and increased permeability of endothelial cells—all essential processes for the sprouting of new blood vessels from existing ones.

By blocking the initial VEGF-A/VEGFR2 interaction, Pulocimab effectively shuts down this entire pro-angiogenic signaling program.[1] This disruption of tumor-associated neoangiogenesis has profound consequences for the tumor. It curtails the development of the vascular network required to supply the rapidly proliferating cancer cells with oxygen and nutrients, leading to a state of metabolic stress, hypoxia, and ultimately, apoptotic or necrotic cancer cell death.[1] Preclinical studies have validated this mechanism, demonstrating Pulocimab's strong binding activity to VEGFR2, its efficient blockade of VEGF binding, and consequent dose-dependent anti-tumor activity

in vitro.[1] This targeted anti-angiogenic strategy has been an essential and validated approach in cancer treatment for decades, and Pulocimab represents a modern iteration of this therapeutic class.

2.2. Pharmacokinetic (PK) and Pharmacodynamic (PD) Properties

The initial characterization of Pulocimab's behavior in humans was established in the first-in-human (FIH), multicenter, open-label Phase I clinical trial, NCT04547205.[10] This study was crucial for understanding the drug's absorption, distribution, metabolism, and excretion (ADME) profile, as well as its direct effect on its biological target.

2.2.1. Pharmacokinetics

The study revealed that Pulocimab exhibits an "approximately linear PK exposure" following intravenous administration, particularly within the dose range of 2 mg/kg to 12 mg/kg.[10] Linearity in pharmacokinetics is a highly desirable property for a therapeutic antibody. It signifies that key PK parameters, such as clearance and volume of distribution, remain constant as the dose is increased. This leads to a predictable and proportional increase in drug concentration (e.g.,

Cmax​ and AUC) with an increase in dose. Such predictability simplifies dose selection and titration, reduces the risk of unexpected accumulation or toxicity, and facilitates the development of reliable dosing regimens for later-phase trials.

2.2.2. Pharmacodynamics

Pharmacodynamic analyses conducted during the FIH study demonstrated "rapid target engagement".[10] This finding indicates that shortly after administration, Pulocimab effectively reaches its site of action in the circulatory system and binds to its intended molecular target, VEGFR2, on endothelial cells. Rapid and efficient target engagement is a prerequisite for therapeutic efficacy, confirming that the drug is performing its intended biological function

in vivo.

2.2.3. Recommended Phase II Dose (RP2D) Selection

A primary objective of the Phase I study was to determine the optimal dose and schedule to carry forward into subsequent phases of development. Based on an integrated assessment of the safety profile, the linear and predictable PK data, the evidence of rapid PD target engagement, and the preliminary signals of anti-tumor activity, the investigators established two distinct Recommended Phase II Doses (RP2D):

• 12 mg/kg administered intravenously every 2 weeks (Q2W) [10]
• 15 mg/kg administered intravenously every 3 weeks (Q3W) [10]

The establishment of two viable dosing schedules is not merely a technical outcome but a significant strategic advantage for the drug's development. Many oncology treatments, particularly combination therapies, involve agents with differing administration frequencies. For instance, paclitaxel can be given weekly or every three weeks, while many immunotherapy agents like cadonilimab are often dosed every three weeks.[7] Having validated both a Q2W and a Q3W regimen for Pulocimab provides crucial flexibility. It allows clinical trial designers to select the Pulocimab schedule that best aligns with the dosing of its combination partners, thereby synchronizing treatment days. This logistical simplification can enhance patient convenience, improve adherence to complex protocols, and streamline the operational aspects of administering multi-drug regimens—all of which are important considerations in the design of large, pivotal clinical trials.

3. The Clinical Development Program: Targeting Immunotherapy Resistance

The clinical development of Pulocimab is sharply focused on its use as a combination agent to address the significant and growing challenge of resistance to immunotherapy. The program spans several solid tumor types, with the most advanced investigations targeting gastric/gastroesophageal junction (G/GEJ) adenocarcinoma and non-small cell lung cancer (NSCLC).

Table 2: Summary of Key Clinical Trials for Pulocimab (AK109)

NCT Identifier	Phase	Indication(s)	Key Combination Agent(s)	Status	Primary Purpose
NCT04547205	Phase I	Advanced Solid Tumors	Monotherapy	Completed	Safety, PK/PD, RP2D
NCT04982276	Phase Ib/II	G/GEJ Adenocarcinoma (2nd Line)	Cadonilimab, Paclitaxel	Recruiting	Safety, Efficacy
NCT06341335	Phase III	G/GEJ Adenocarcinoma (2nd Line)	Cadonilimab, Paclitaxel	Recruiting	Efficacy (PFS)
N/A	Phase Ib/II	IO-Resistant NSCLC	Cadonilimab	Phase III Planned	Efficacy (OS, PFS)
NCT05142423	Phase Ib/II	Advanced Solid Tumors	Cadonilimab	Recruiting	Safety, Efficacy

3.1. Gastric and Gastroesophageal Junction (G/GEJ) Adenocarcinoma: A Second-Line Strategy

Pulocimab is being evaluated as part of a triplet therapy for patients with advanced G/GEJ cancer who have already progressed on first-line standard of care, which now commonly includes an immune checkpoint inhibitor combined with chemotherapy.

3.1.1. Phase Ib/II Trial (NCT04982276): Establishing Proof-of-Concept

This multicenter, randomized, double-blind Phase Ib/II study was designed to provide the initial proof-of-concept for combining Pulocimab with both immunotherapy and chemotherapy in a resistant setting.[7] The trial enrolled patients with advanced G/GEJ adenocarcinoma whose disease had progressed after treatment with a first-line regimen containing an anti-PD-1 monoclonal antibody and chemotherapy, a population with a poor prognosis and limited effective treatment options.[7]

The expansion phase of the study randomized patients to one of two arms:

• Experimental Arm: Cadonilimab (PD-1/CTLA-4 bispecific) + Pulocimab (VEGFR-2 mAb) + paclitaxel
• Control Arm: Placebo + Pulocimab (VEGFR-2 mAb) + paclitaxel

This design was specifically chosen to isolate the therapeutic contribution of adding dual PD-1/CTLA-4 blockade (cadonilimab) to a backbone of anti-angiogenic therapy and chemotherapy. As of the data cutoff on October 30, 2023, with a median follow-up of 7.3 months, the study demonstrated a clear benefit for the experimental arm, as detailed in Table 4.[7]

Table 4: Efficacy Results from Phase Ib/II Study (NCT04982276) in G/GEJ Cancer

Efficacy Endpoint	Experimental Arm (Cadonilimab + Pulocimab + Paclitaxel)	Control Arm (Placebo + Pulocimab + Paclitaxel)
Objective Response Rate (ORR)	48.0% (12/25)	35.7% (10/28)
Disease Control Rate (DCR)	96.0% (24/25)	92.9% (26/28)
Median Progression-Free Survival (mPFS)	6.8 months [95% CI 4.1, 11.2]	4.9 months [95% CI 3.2, 7.1]
Median Duration of Response (mDoR)	Not Reached	4.0 months [95% CI 1.58, NE]
Source: 7

The results showed a clinically meaningful improvement in ORR and a 1.9-month extension in median PFS with the addition of cadonilimab. The safety profile was deemed manageable, providing strong rationale to proceed to a larger, confirmatory trial.[7]

3.1.2. Pivotal Phase III Trial (NCT06341335): The Path to Confirmation

Building on the encouraging Phase II results, Akeso initiated a large-scale, pivotal Phase III trial (NCT06341335) to definitively establish the efficacy and safety of the triplet regimen.[19] This randomized, double-blind, multicenter study is designed to enroll approximately 506 patients with the same indication: advanced or metastatic G/GEJ adenocarcinoma that has failed first-line immunochemotherapy.[21]

A crucial evolution in the study design is the change in the control arm. The Phase III trial compares:

• Experimental Arm: Cadonilimab + Pulocimab + paclitaxel
• Control Arm: Placebo + paclitaxel

This represents a significant strategic shift from the Phase II study. The earlier trial aimed to prove the value of adding cadonilimab to a Pulocimab/paclitaxel backbone. The Phase III trial, however, is designed to answer a more ambitious and commercially relevant question: is the entire triplet combination superior to the existing second-line standard of care, paclitaxel (often paired with the anti-VEGFR2 agent ramucirumab)?.[25] The primary endpoint for this study is Progression-Free Survival (PFS), and it is currently recruiting patients with an estimated primary completion date of November 2026.[21] A positive outcome from this trial could establish the cadonilimab/Pulocimab/paclitaxel regimen as a new global standard of care for this patient population.

3.2. Non-Small Cell Lung Cancer (NSCLC): A Potential Chemotherapy-Free Breakthrough

In NSCLC, the combination of Pulocimab and cadonilimab is being investigated as a novel, chemotherapy-free approach for patients who have developed resistance to first-line immunotherapy.

3.2.1. Phase Ib/II WCLC 2025 Data: Promising Survival in IO-Resistant Disease

Data from a Phase Ib/II study presented at the 2025 World Conference on Lung Cancer (WCLC) highlighted the potential of the Pulocimab and cadonilimab doublet.[4] The study targeted patients with advanced or metastatic NSCLC whose disease had progressed following standard first-line immunotherapy-based treatment. This is a population with a major unmet need, as 60-70% of patients experience progression within a year, and the subsequent standard therapy, docetaxel chemotherapy, offers limited benefit.[4]

The results, based on a median follow-up of 16.7 months as of January 13, 2025, were highly encouraging, particularly regarding overall survival.[9]

Table 3: Efficacy Results from Phase Ib/II Study in IO-Resistant NSCLC (WCLC 2025 Data)

Efficacy Endpoint	Overall Population	Squamous Subgroup	Non-Squamous Subgroup
Median Overall Survival (mOS)	15.6 months	16.7 months	12.8 months
Median Progression-Free Survival (mPFS)	5.8 months	7.1 months	5.5 months
Objective Response Rate (ORR)	N/A	11.5%	14.3%
Disease Control Rate (DCR)	N/A	96.2%	95.2%
Source: 4

The mOS of 15.6 months in the overall IO-resistant population is a strong signal of clinical benefit. The ability to achieve this with a chemotherapy-free regimen is a significant potential advantage, reducing the toxicity burden for patients.[4] In recognition of this potential, the combination therapy received Breakthrough Therapy Designation from China's NMPA for advanced squamous NSCLC progressing after PD-(L)1 inhibitor treatment.[4] Based on these promising data, Akeso is preparing for a pivotal Phase III study in this indication.[4]

3.3. Foundational Evidence: The First-in-Human Study (NCT04547205)

The entire clinical program for Pulocimab was built upon the foundational evidence generated in its FIH Phase I study (NCT04547205).[27] This open-label, single-agent dose-escalation and expansion study enrolled 40 patients with a variety of advanced solid tumors.[10] The patient population was heavily pre-treated, with 57.5% having received two or more prior lines of systemic therapy, making it a challenging cohort in which to demonstrate efficacy.[20]

Despite this, Pulocimab monotherapy showed encouraging signals of anti-tumor activity. Among the 40 participants, 4 (10%) achieved a partial response (PR), and an additional 21 (52.5%) achieved stable disease (SD). This resulted in an objective response rate of 10% and a disease control rate of 62.5%.[10] Most importantly, the study established a manageable safety profile, observed no dose-limiting toxicities, and successfully identified the RP2D (12 mg/kg Q2W and 15 mg/kg Q3W) that would be used in all subsequent combination trials.[2]

3.4. Exploratory Trials and Future Indications

The development program extends beyond G/GEJ cancer and NSCLC. An ongoing open-label Phase Ib/II basket study (NCT05142423) is evaluating the combination of Pulocimab and cadonilimab in a broader range of advanced solid tumors, including colorectal cancer and hepatocellular carcinoma (HCC), to explore the combination's activity across different cancer types.[2] Preliminary data has suggested that the combination also holds promise in other treatment-resistant settings, including IO-resistant HCC, indicating a potentially broad applicability for this therapeutic strategy.[4]

4. Consolidated Safety and Tolerability Analysis

The safety and tolerability of an investigational agent are paramount to its potential clinical utility. Across its clinical development program, Pulocimab has demonstrated a safety profile that has been consistently described by investigators as "manageable".[8] The observed adverse events are largely predictable and align with the known on-target effects of inhibiting the VEGFR2 signaling pathway.

4.1. Overview of Treatment-Related Adverse Events (TRAEs)

Data from both the single-agent FIH study and the combination therapy trials provide a comprehensive picture of Pulocimab's safety profile.

• Single-Agent Profile (NCT04547205): In the foundational Phase I study where Pulocimab was administered as monotherapy to 40 patients, treatment-related adverse events were common, with 38 patients (95%) reporting at least one TRAE. The most frequently reported TRAEs of any grade were proteinuria (60%), hypertension (32.5%), increased aspartate transaminase (AST) (27.5%), thrombopenia (25%), and anemia (25%). More clinically significant Grade ≥3 TRAEs occurred in 10 patients (25%), indicating that while common, the majority of adverse events were of low severity.[10]
• Combination Therapy Profile (NCT04982276): In the Phase Ib/II study in G/GEJ cancer, where Pulocimab was combined with cadonilimab and paclitaxel, the safety profile reflected the toxicities of all three components. For the triplet regimen, the most common Grade 3-4 TRAEs occurring in ≥10% of patients were neutrophil count decreased (27.6%), white blood cell count decreased (10.3%), and hypertension (13.8%).[7] The hematological toxicities (neutropenia, leukopenia) are well-known side effects of paclitaxel chemotherapy, while hypertension is a classic effect of VEGFR2 inhibition. Importantly, investigators concluded that no new or unexpected safety signals were identified from the combination.[7]

Table 5: Consolidated Safety Profile of Pulocimab (as single agent and in combination)

Adverse Event (AE)	Frequency (Any Grade) - Single Agent (NCT04547205)	Frequency (Grade ≥3) - Single Agent (NCT04547205)	Frequency (Grade 3-4) - Combination (NCT04982276)
AESIs
Proteinuria	60%	Not Specified	Not Specified
Hypertension	32.5%	Not Specified	13.8%
Hemorrhage	32.5%	Not Specified	Not Specified
Common TRAEs
Neutrophil count decreased	Not Specified	Not Specified	27.6%
White blood cell count decreased	Not Specified	Not Specified	10.3%
Anemia	25%	Part of 25% total	Not Specified
Thrombopenia	25%	Part of 25% total	Not Specified
Increased AST	27.5%	Part of 25% total	Not Specified
Asthenia	25%	Not Specified	Not Specified
Source: 7

4.2. Adverse Events of Special Interest (AESIs)

Given Pulocimab's mechanism of action, particular attention is paid to adverse events of special interest that are known to be associated with the inhibition of the VEGF/VEGFR pathway. In the FIH study, 28 patients (70%) reported at least one AESI. The most common were:

• Proteinuria (60%): The presence of excess protein in the urine, resulting from effects on the glomerular filtration barrier in the kidneys.
• Hypertension (32.5%): Elevated blood pressure, thought to be caused by a decrease in nitric oxide production and an increase in peripheral vascular resistance.
• Hemorrhage (32.5%): Bleeding events, which were reported to be mainly minor, such as gum bleeding and urethrorrhagia.[10]

The profile of these AESIs is highly significant because it is predictable. Hypertension, proteinuria, and an increased risk of bleeding are the hallmark toxicities of the entire class of VEGFR inhibitors, including approved drugs like bevacizumab, ramucirumab, and numerous small-molecule tyrosine kinase inhibitors. This predictability is clinically advantageous. It means that oncologists are already well-versed in the necessary monitoring protocols (e.g., regular blood pressure checks, routine urinalysis) and management strategies (e.g., initiation of anti-hypertensive medications, dose interruption for severe proteinuria). The absence of novel or unexpected safety signals suggests that the toxicity of Pulocimab is on-target and does not introduce new management challenges, which is a favorable characteristic for a drug under development.

4.3. Drug Interactions

The provided documentation does not contain results from formal drug-drug interaction (DDI) studies specifically conducted for Pulocimab. This represents a current data gap in its publicly available development profile. However, an assessment of potential interactions can be inferred from the agents with which it is being combined in clinical trials.

Pulocimab is being studied extensively with paclitaxel, a taxane-based cytotoxic chemotherapy agent.[7] Paclitaxel is known to cause myelosuppression, leading to decreased counts of neutrophils and platelets.[29] The safety data from the G/GEJ combination trial, which shows high rates of Grade 3-4 neutropenia, reflects this expected overlapping toxicity.[8] Monoclonal antibodies like Pulocimab generally have a lower potential for pharmacokinetic interactions mediated by cytochrome P450 (CYP) enzymes compared to small-molecule drugs. However, pharmacodynamic interactions, where two drugs have additive or synergistic effects on the same physiological systems, are clearly relevant.

The other key combination partner, cadonilimab, is a bispecific monoclonal antibody. Immunotherapies as a class can have numerous moderate interactions, particularly with other drugs that modulate the immune system (e.g., corticosteroids, vaccines).[30] While the specific interaction profile of the Pulocimab/cadonilimab combination has not been detailed, the manageable safety profile observed in trials suggests an absence of severe, synergistic toxicities to date. Nevertheless, a formal characterization of the DDI potential of Pulocimab, especially concerning its effects on the metabolism of co-administered chemotherapies, will be an important component of its complete regulatory submission package.

5. Strategic Imperative: The Synergy of VEGFR2 and PD-1/CTLA-4 Blockade

5.1. Scientific Rationale for Combination

The clinical development strategy for Pulocimab is not centered on its activity as a single agent but on its role as a critical potentiator for advanced immunotherapy. The core of Akeso's program is the hypothesis that combining VEGFR2 inhibition with dual PD-1 and CTLA-4 blockade can synergistically overcome immunotherapy resistance. This strategy is designed to fundamentally alter the tumor microenvironment (TME), transforming it from a state that is hostile to immune cells (an "immunologically cold" tumor) to one that is permissive to a robust anti-tumor immune attack (an "immunologically hot" tumor).

Resistance to immune checkpoint inhibitors is frequently associated with an "immune-excluded" or "immune-desert" phenotype, where cytotoxic T-lymphocytes are either unable to penetrate the tumor stroma or are absent altogether.[26] The VEGF/VEGFR2 signaling pathway is a key contributor to this immunosuppressive TME through several mechanisms. First, it promotes the development of an abnormal, tortuous, and highly permeable tumor vasculature, which acts as a physical barrier, impeding the efficient trafficking and infiltration of T-cells into the tumor core. Second, VEGF signaling can directly promote an immunosuppressive cellular milieu by recruiting regulatory T-cells (Tregs), myeloid-derived suppressor cells (MDSCs), and M2-polarized tumor-associated macrophages, all of which actively suppress the function of cytotoxic T-cells.

By administering Pulocimab to block VEGFR2, the aim is to reverse these effects. Inhibition of VEGFR2 signaling can lead to "vascular normalization," resulting in a more organized and less permeable vessel network that facilitates T-cell extravasation and infiltration. Simultaneously, it can reduce the recruitment of immunosuppressive cell populations, shifting the balance of the TME toward an anti-tumor inflammatory state.

In this remodeled, more favorable "battlefield," the therapeutic effect of cadonilimab can be fully realized. Cadonilimab is a powerful immunotherapy agent that simultaneously blocks two distinct inhibitory checkpoints on T-cells. The PD-1/PD-L1 axis is a primary mechanism of T-cell exhaustion within the tumor itself, while the CTLA-4 pathway acts earlier to dampen the initial priming and activation of T-cells in lymph nodes. By blocking both pathways, cadonilimab is designed to unleash a more potent and durable anti-tumor T-cell response than a PD-1 inhibitor alone.

Thus, Pulocimab acts as the primer, remodeling the TME to allow T-cells to enter the tumor and function effectively. Cadonilimab then acts as the primary effector, maximally activating these T-cells to recognize and eliminate cancer cells. This proposed synergy is the scientific foundation for testing the combination specifically in IO-resistant patient populations, where single-agent checkpoint inhibition has already failed.

5.2. Akeso's Broader Platform Strategy

The development of the Pulocimab/cadonilimab combination is a clear manifestation of Akeso's overarching corporate strategy. The company has explicitly focused its R&D efforts on creating therapies that leverage dual-target or synergistic mechanisms to address the most pressing clinical challenges, such as the limited efficacy of or acquired resistance to single-target agents.[4]

This philosophy is evident across their pipeline. Cadonilimab itself is a bispecific antibody that combines two immunotherapies into one molecule. Another key asset, ivonescimab, is a bispecific antibody that simultaneously targets PD-1 and VEGF, integrating the anti-tumor immune response with anti-angiogenic effects in a single agent.[4] Pulocimab, as a highly specific anti-VEGFR2 antibody, serves as a perfect modular component within this portfolio. It can be combined with their core immunotherapy assets like cadonilimab to create a powerful, synergistic regimen tailored to specific resistance mechanisms. This platform approach allows Akeso to build a versatile oncology franchise capable of addressing different stages of disease and overcoming therapeutic hurdles.

6. Regulatory and Competitive Landscape

6.1. Current Regulatory Status

As an investigational drug, Pulocimab has not yet received marketing authorization from any major global regulatory agency, including the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or Australia's Therapeutic Goods Administration (TGA).[32] Its entire clinical program is currently conducted under Investigational New Drug (IND) applications or their international equivalents.

However, the program has achieved a significant regulatory milestone in China. The combination of cadonilimab and Pulocimab was granted a Breakthrough Therapy Designation by the National Medical Products Administration (NMPA) for the treatment of advanced squamous NSCLC in patients whose disease has progressed following treatment with a PD-(L)1 inhibitor.[4] This designation is reserved for therapies that have shown substantial improvement over available therapies on a clinically significant endpoint in preliminary clinical evidence. It is a strong endorsement from the regulatory agency and can confer benefits such as enhanced communication with regulators and an expedited development and review process in China.

6.2. Path to Market: Lessons from Penpulimab

Akeso's path forward with Pulocimab can be informed by its recent success in navigating the global regulatory landscape with another of its internally developed antibodies, penpulimab (AK105), an anti-PD-1 monoclonal antibody. In April 2025, penpulimab received full approval from the U.S. FDA for two indications in nasopharyngeal carcinoma (NPC): as a first-line treatment in combination with chemotherapy, and as a later-line monotherapy.[33]

This achievement was a landmark for Akeso, representing its first FDA-approved product and validating its capability to execute drug development and manufacturing processes that meet the highest international standards.[34] The approval was based on data from robust, international, multicenter Phase III clinical trials that enrolled diverse patient populations, demonstrating the company's ability to manage complex global studies.[34] Furthermore, the penpulimab application benefited from multiple FDA expedited programs, including Fast Track, Breakthrough Therapy, and Orphan Drug designations, showcasing Akeso's proficiency in engaging with the regulatory system to accelerate the availability of promising new medicines.[35]

This successful experience provides a clear and proven playbook for the Pulocimab program. Akeso has demonstrated it possesses the requisite expertise to conduct the large, global Phase III trials needed for registration in the U.S. and other major markets. It is highly probable that a similar strategy will be employed for the Pulocimab/cadonilimab combination: pursue robust, global Phase III trials (such as the ongoing NCT06341335 and the planned NSCLC study), engage with the FDA and other agencies early, and leverage the high unmet medical need in IO-resistant populations to seek expedited review pathways. The success with penpulimab significantly de-risks the regulatory execution phase of Pulocimab's future development.

6.3. Competitive Positioning

The Pulocimab combination regimens are being developed to enter therapeutic areas with significant unmet needs, positioning them to potentially displace or redefine the existing standards of care.

• Immunotherapy-Resistant NSCLC: For patients with advanced NSCLC without driver mutations who progress on first-line chemoimmunotherapy, the current established standard of care is single-agent docetaxel chemotherapy.[4] While it is the benchmark, docetaxel provides only modest efficacy and is associated with substantial toxicity. The Pulocimab/cadonilimab doublet, with its promising mOS of 15.6 months in a Phase II study and its potential as a chemotherapy-free option, is positioned as a direct and potentially superior alternative.[9] If the upcoming Phase III trial confirms a significant survival benefit, this combination could readily become the new standard of care for this large and growing patient population.
• Second-Line G/GEJ Adenocarcinoma: The established global standard of care for second-line treatment of advanced G/GEJ adenocarcinoma is the combination of the anti-VEGFR2 monoclonal antibody ramucirumab plus paclitaxel.[25] This regimen was approved based on the RAINBOW trial, which demonstrated a median PFS of 4.4 months and a median OS of 9.6 months.[25] The triplet combination of Pulocimab, cadonilimab, and paclitaxel will compete directly with this standard. The Phase II data for the triplet showed a median PFS of 6.8 months, suggesting a potentially superior efficacy profile.[7] A successful Phase III trial (NCT06341335) that confirms a statistically significant and clinically meaningful improvement over the paclitaxel backbone would position this triplet as the new, more effective second-line standard.

7. Expert Assessment and Future Outlook

7.1. Critical Appraisal of Clinical Data

The clinical development program for Pulocimab, centered on its synergy with cadonilimab, presents a compelling case built on a strong scientific rationale and encouraging, albeit early, clinical results.

• Strengths: The primary strength of the program lies in its strategic focus. By targeting the well-defined and critical unmet need of immunotherapy resistance, Akeso has positioned Pulocimab to address a major challenge in oncology. The clinical data generated to date, while from Phase II studies, shows a remarkable consistency in its signal of efficacy across two different, hard-to-treat cancer types (G/GEJ and NSCLC). The observed improvements in PFS and OS are clinically meaningful and suggest true synergistic activity. Furthermore, the safety profile appears to be manageable and, importantly, predictable, with adverse events that are characteristic of the drug's known mechanism and familiar to clinicians.
• Limitations: The primary limitation is the maturity of the data. For the G/GEJ cancer trial, the overall survival data, which is the gold standard for approval in oncology, was not yet mature at the time of the last report.[7] While the trends are favorable, confirmation of a statistically significant OS benefit in the ongoing Phase III trial is essential. The data for both indications have been presented at scientific conferences but await full publication in peer-reviewed journals, which will allow for a more rigorous and independent scrutiny of the study design, conduct, and results. As with all industry-sponsored trials, the potential for bias must be considered until the full, peer-reviewed data are available.

7.2. Unanswered Questions and Data Gaps

Despite the promising results, several critical questions remain that will be pivotal for Pulocimab's future.

1. Confirmation of Overall Survival Benefit: Will the promising interim survival trends observed in the Phase II studies translate into statistically significant and clinically meaningful overall survival benefits in the larger, more definitive Phase III trials? This is the single most important question for regulatory approval and clinical adoption.
2. Long-Term Safety Profile: What is the long-term safety and tolerability of continuous exposure to the triplet combination in G/GEJ cancer and the doublet in NSCLC? Understanding the cumulative toxicity and the incidence of rare but serious adverse events over time is crucial.
3. Biomarker Development: Beyond a history of IO-resistance, are there specific molecular or immunological biomarkers that can predict which patients are most likely to derive exceptional benefit from this combination? Identifying a predictive biomarker could help optimize patient selection and further enhance the therapeutic index.
4. Formal Interaction Studies: What is the formal drug-drug interaction profile of Pulocimab? Characterizing its potential to affect the pharmacokinetics of co-administered agents like paclitaxel will be necessary for comprehensive labeling and safe clinical use.

7.3. Concluding Remarks and Recommendations

Pulocimab should not be viewed as a standalone anti-angiogenic agent but rather as a critical enabler within Akeso Biopharma's innovative immunotherapy portfolio. Its true value and therapeutic potential are unlocked through its scientifically rational and synergistic combination with the dual checkpoint inhibitor cadonilimab. The strategy of using VEGFR2 inhibition to remodel the tumor microenvironment and overcome resistance to immunotherapy is one of the most promising approaches currently being explored in oncology.

The encouraging efficacy and manageable safety data from Phase II trials provide a strong foundation for this strategy. However, the ultimate determinant of Pulocimab's place in cancer therapy will be the successful execution and positive outcome of the ongoing and planned pivotal Phase III trials. If these trials confirm a significant survival advantage, the Pulocimab/cadonilimab combination has the potential to fundamentally reshape the treatment paradigm and establish a new global standard of care for patients with advanced, immunotherapy-resistant non-small cell lung cancer and gastric/gastroesophageal junction cancers. The program represents a sophisticated and promising approach to tackling one of the most difficult challenges in modern cancer treatment.

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