MSD, the maker of the global "king of medicine" - Keytruda, made headlines at the end of last year by investing USD 588 million in an advance payment and USD 2.7 billion in potential milestone payments to acquire the tumor immunotherapy LM-299 from the Chinese company LaNova Medicines. This deal highlights the growing attention in the pharmaceutical development field towards oncology targeting the dual PD-(L)1 and VEGF pathways. PD-(L)1 and VEGF (vascular endothelial growth factor) bispecific antibody therapies are considered a key direction for future tumor treatments, attracting increasing global interest due to their unique mechanism of action and promising clinical data. As a result, more and more pharmaceutical companies worldwide are focusing on this area, with China playing a crucial role in its field.

1.  Mechanism of Action of PD-(L)1 and VEGF Combination Therapy

PD-(L)1 inhibitors restore the immune system's ability to recognize and attack tumor cells by blocking the interaction between the PD-L1 molecules expressed on tumor cells and the PD-1 receptors on immune cells. However, the abnormal blood vessel development in the tumor microenvironment can inhibit immune cell infiltration and provide nutritional support to tumor cells. VEGF, as a major regulator of angiogenesis, plays a crucial role in this process. By inhibiting VEGF, the normal blood vessel structure of the tumor tissue can be restored, enhancing immune cell penetration into the tumor and synergizing with PD-(L)1 inhibitors to strengthen the anti-tumor immune response.

For this reason, PD-(L)1 and VEGF dual-target bispecific antibody therapies have garnered widespread attention. These therapies combine immune checkpoint inhibition with anti-angiogenesis, not only directly targeting the tumor but also optimizing the tumor microenvironment from multiple angles to create a synergistic anti-cancer effect. Particularly in patient groups where PD-(L)1 inhibitor single-drug is not highly effective, PD-(L)1/VEGF bispecific antibody has the potential to significantly improve therapeutic effect. Currently, more than 10 PD-(L)1/VEGF bispecific antibody projects are in clinical trials, and early data has shown promising efficacy across various solid tumors, demonstrating significant tumor inhibition effects and the potential for prolonged survival.

2.  Position of Chinese Assets in the Global PD-(L)1/VEGF Competitive Landscape

Globally, the R&D of PD-(L)1 and VEGF bispecific antibody therapies has entered a highly competitive phase. Major pharmaceutical giants and biotech companies have increased their investments to advance the development of related drugs.

Currently, several PD-(L)1 and VEGF bispecific antibody assets targeting different tumor types have entered clinical trials. Among them, the key assets from Summit Therapeutics and BioNTech stand out. MSD's acquisition of LM-299 asset of LaNova Medicines was, to some extent, inspired by Summit Therapeutics, which also licensed the PD1-VEGF drug ivonescimab from another Chinese company, Akeso, Inc. A clinical trial of Ivonescimab showed that it outperformed MSD's "king of medicine" Keytruda in the treatment of non-small cell lung carcinoma (NSCLC), one of the most important indications for which Keytruda has been approved. Ivonescimab's success in this field highlights the potential for PD1-VEGF mechanism drugs to "replace" existing therapies in the future.

In addition to Ivonescimab, BioNTech's PD-L1/VEGF candidate BNT-327 has demonstrated consistent efficacy across various tumors and subgroups, with particularly optimistic data in breast cancer. Not coincidentally, BNT-327 was also an asset acquired through BioNTech's USD 800 million acquisition of the Chinese enterprise Biotheus, with an additional potential performance payment of USD 150 million. This deal was officially completed in February of this year. To date, more than 750 patients have received BNT-327 treatment in clinical trials. Multiple clinical trials are underway to evaluate the effects of BNT-327 as a monotherapy or in combination with other treatments targeting various oncogenic pathways for solid tumor indications. Several global tests are in the planning stages, including three global clinical trials focusing on first-line small cell lung carcinoma (SCLC), non-small cell lung carcinoma (NSCLC), and triple negative breast cancer (TNBC). BNT-327 will also be developed in combination with BioNTech's ADC assets.

3.  Major Global PD-(L)1/VEGF Pipeline Assets

In addition to Ivonescimab and BNT-327 mentioned above, there are at least 11 PD-(L)1/VEGF pipeline assets globally, with Chinese enterprises playing a significant role in nearly all of them.

SCTB14

· Mechanism: PD-1/VEGF

· Developer: Beijing SinoCellTech Biotechnology (SinoCellTech, China)

· Phase: Phase 2/3

· SCTB14 is a PD-1/VEGF asset developed by SinoCellTech, targeting various solid tumors. It is currently undergoing Phase 2/3 trials in combination with pemetrexed and cisplatin/carboplatin for EGFR-mutant locally advanced or metastatic non-squamous non-small cell lung carcinoma (NSCLC).

SSGJ-707

· Mechanism: PD-1/VEGF

· Developer: 3SBio Inc. (China)

· Phase: Phase II

· SSGJ-707 is a PD-1/VEGF oncology asset developed by HanBio Therapeutics, a subsidiary of 3S Guojian Pharmaceutical. It is currently undergoing Phase II clinical research for indications including non-small cell lung carcinoma (NSCLC), advanced or recurrent endometrial cancer, and metastatic colorectal cancer. 

RC148

· Mechanism: PD-1/VEGF

· Developer: RemeGen Biosciences

· Phase: Phase II

· RC-148 is a PD-1/VEGF asset developed by RemeGen Biosciences, headquartered in Yantai, China. It is currently in Phase II development for the treatment of breast cancer.

JS207

· Mechanism: PD-1/VEGF

· Developer: DotBio (Singapore)/Junshi Biosciences (Top Alliance, China)

· Phase: Phase II

· JS207 is a PD-1/VEGF asset jointly developed by Singapore-based DotBio and Junshi Biosciences. It is a bispecific antibody designed by combining DotBio's anti-VEGF module with Junshi Biosciences' anti-PD-1 antibody. The asset is currently in Phase II clinical trials in China for non-small cell lung carcinoma (NSCLC), targeting advanced disease, combination therapy, second-line or later treatment, metastatic, and recurrent cases.

Sotiburafusp alpha

· Mechanism: PD-L1/VEGF

· Developer: Huabo Biopharm (China)

· Phase: Phase II

· Sotiburafusp alpha is a PD-L1/VEGF-targeting bispecific fusion protein developed by Huabo Biopharm. It is formed by fusing a humanized VEGFR-1 extracellular structural domain fragment with a humanized IgG1-kappa anti-human PD-L1 heavy chain variant through a polypeptide linker (101GGSGGSGGSGGSGGS115). Sotiburafusp alpha is also an angiogenesis inhibitor. It is currently undergoing Phase II clinical trials in the United States and China for non-small cell lung carcinoma (NSCLC) and endometrial cancer.

Palverafusp alpha

· Mechanism: PD-L1/VEGF

· Developer: Instil Bio (United States)/ImmuneOnco Biopharma (China)

· Phase: Phase II

· Palverafusp alpha is a PD-L1/VEGF bispecific fusion protein jointly developed by ImmuneOnco and the United States Instil Bio. It is currently in Phase II development for various solid tumors, including non-small cell lung carcinoma (NSCLC), triple negative breast cancer, and soft tissue sarcoma. On August 1, 2024, ImmuneOnco and Instil Bio reached an agreement, with the latter acquiring the development and commercialization rights for Palverafusp alpha outside the Greater China region. ImmuneOnco will retain the development and commercialization rights for Palverafusp alpha in the Greater China region, including Taiwan, Macau, and Hong Kong, China. On March 6, 2025, the clinical trial application for the combination of Timdarpacept and Palverafusp alpha for advanced malignant tumors was officially approved by the National Medical Products Administration (NMPA). Timdarpacept is China's first SIRPα-Fc fusion protein to enter clinical stages and is currently being used in combination with other drugs to treat various hematologic tumors and solid tumors.

AP505

· Mechanism: PD-L1/VEGF

· Developer: Tasly (China)/AP (AP Biosciences, Taiwan)

· Phase: Phase II

· AP505 is a PD-L1/VEGF bispecific antibody developed by Taiwan-based AP Biosciences. In 2019, it was licensed to Tasly Biotech, which obtained exclusive rights for clinical development, production, and sales in Chinese Mainland, as well as in the Hong Kong, S.A.R., China and Macau Special Administrative Regions. It is currently undergoing multiple clinical researches in Chinese Mainland and Taiwan, China for various solid tumors, including colorectal cancer, non-small cell lung carcinoma (NSCLC), and hepatocellular carcinoma.

 MHB039A

· Mechanism: PD-1/VEGF

· Developer: Minghui Pharmaceutical (China)

· Phase: Phase 1/2

· MHB039A, researched and developed by Minghui Pharmaceutical, is a novel PD-1/VEGF bispecific antibody. It exhibits complete blocking activity against both PD-1 and VEGF, with superior PD-1 activity compared to competing antibodies. The unique molecular design enhances the drug's manufacturability and physicochemical properties, providing high protein yield and stability. MHB039A can be combined with various treatment modalities, including immunity antitumor drugs, small molecule inhibitors, ADCs, vaccines, and T-cell engagers.

LM-299

· Mechanism: PD-1/VEGF

· Developer: MSD/LaNova Medicines (China)

· Phase: Phase 1/2

· LM-299 is a PD-1/VEGF bispecific antibody oncology asset that MSD acquired from LaNova Medicines last year for an advance payment of USD 588 million. LM-299 features a differentiated molecular design, including an anti-VEGF antibody linked to two C-terminal single-domain anti-PD-1 antibodies. It is currently undergoing Phase I trials in China for solid tumors.

AI-081

· Mechanism: PD-1/VEGF

· Developer: AcroImmune Group (China)

· Phase: Phase 1/2

· AI-081 is a potential best-in-class PD-1/VEGF bispecific antibody developed by AcroImmune Group (which merged with OncoC4 to form OncoC4 Inc. in September 2024). It has demonstrated high potency and in vivo anti-tumor activity in preclinical models. AI-081 utilizes a head-to-tail bispecific configuration to achieve more robust synergistic interactions, along with additional Fc silencing mutations to protect immune effector cells. The IND application for AI-081 was approved by the FDA at the end of last year, and it is currently undergoing Phase I/II clinical research for solid tumors.

SG1408

· Mechanism: PD-L1/VEGF

· Developer: Sumgen Biotech (China)

· Phase: Phase I

· SG1408 is a PD-L1/VEGF bispecific antibody developed by Sumgen Biotech. It is currently undergoing Phase I clinical trials in China for the treatment of advanced solid tumors.

CVL006

· Mechanism: PD-L1/VEGF

· Developer: Convalife (China)

· Phase: Phase I

· CVL006 is a PD-L1/VEGF bispecific antibody developed by Convalife. Compared to the PD-L1 inhibitor Atezolizumab (Tecentriq), CVL006 has demonstrated superior anti-tumor effects in mouse models, with greater tumor growth inhibition and reduced angiogenesis. In comparison to Ivonescimab, CVL006 also shows more impressive anti-tumor activity in vivo.

CR-001 (Preclinical): PD-1/VEGF; Crescent Biopharma (United States)/Paragon Therapeutics (United States)

CTX-10726 (Preclinical): PD-1/VEGF; Compass Therapeutics (United States)

HX016-9 (Preclinical): PD-1/VEGF; Hanx Biopharmaceuticals (China)

NY-500 (Preclinical): PD-1/VEGF; NAYA Biosciences (United States)

WO2024017281 (Preclinical): PD-1/VEGF; Minghui Pharmaceutical (China)

Unnamed (Preclinical): PD-1/VEGF; Biox-Vision (China)

BB-203 (Preclinical): PD-L1/VEGF; Bright Biologics (United States)

HX016-7 (Preclinical): PD-L1/VEGF; Hanx Biopharmaceuticals (China)

ILB-2201 (Preclinical) PD-L1/VEGF; Innolake Biopharm (China)

IMM2518 (Preclinical): PD-L1/VEGF; ImmuneOnco Biopharma (China)

JMB2003 (Preclinical): PD-L1/VEGF; Jimincare (China)

PB203 (Preclinical): PD-L1/VEGF; Panolos Bioscience (South Korea)

PD x VEGF Trap (Preclinical): PD-L1/VEGF; Immunowake (United States)

SPX-308 (Preclinical): PD-L1/VEGF; Sparx Biopharmaceutical (United States)

SPX-603 (Preclinical): PD-L1/VEGF; Sparx Biopharmaceutical (United States)

WO2021244371 (Preclinical): PD-L1/VEGF; 3SBio Inc. (China)

WO2024140996A (Preclinical): PD-L1/VEGF; Henlius Biotech (China)

4.  Analysis of Chinese Enterprises' Enthusiasm for Developing PD-(L)1/VEGF Oncology Products

The innovation of PD-(L)1 x VEGF bispecific antibodies lies in their ability to simultaneously target tumor immune evasion mechanisms (through PD-(L)1 inhibition) and tumor angiogenesis (through VEGF inhibition). These bispecific antibodies combine the dual effects of immune modulation and anti-angiogenesis within a single molecule. Compared to traditional combination therapies, they not only reduce the risk of side effects caused by drug interactions but also provide more precise tumor inhibition effects. Chinese enterprises recognize the potential of these drugs, particularly for cancer types that require improvement in the immune microenvironment, such as liver cancer. Developing these antibodies can offer significant clinical advantages.

Studies have shown that the response rate to VEGF inhibitors is higher in the Asian patient population compared to other groups. Chinese enterprises recognize this biological characteristic and aim to leverage this advantage by developing PD-(L)1 x VEGF therapies. This combination therapy not only enhances efficacy but also better serves Asian patients by providing differentiated treatment options. The potential of PD-(L)1 x VEGF therapy is particularly evident in tumors such as liver cancer and gastric cancer, which are more sensitive to VEGF inhibition.

China has a large patient population for certain types of cancers, such as liver cancer, where VEGF inhibitors have been proven effective. Liver cancer is highly prevalent in China, with limited traditional treatment options and suboptimal efficacy. Therefore, the combination therapy of PD-(L)1 x VEGF, particularly in advanced liver cancer, has significant clinical value. By focusing on this specific patient population, Chinese enterprises can demonstrate the drug efficacy in a shorter period, thereby accelerating clinical progress.

PD-(L)1 inhibitors have been widely used as monotherapies, particularly in common cancers such as lung cancer. However, their efficacy is limited in patients with low PD-L1 expression. Additionally, the PD-(L)1 market has become saturated. By developing bispecific antibodies with broader and more precise applications, Chinese enterprises can effectively differentiate themselves and avoid the intense competition in the traditional PD-(L)1 therapy market. It is expected that by 2027, the PD-(L)1 market could exceed USD 60 billion, and PD-(L)1 x VEGF therapies have the potential to replace PD-(L)1 as the leading treatment.

5.  Future Outlook of Bispecific/Multispecific Antibody Research

Looking to the future, bispecific antibodies are expected to break the limitations of monotherapy, especially for patients in certain subgroups of indications who have poor efficacy with existing single-target treatments. By simultaneously targeting multiple pathways, bispecific antibodies can achieve a more comprehensive tumor inhibition effect and reduce the tumor's immune evasion mechanisms. This not only makes PD-(L)1 x VEGF drugs highly anticipated but also paves the way for the diversified development of future immuno-oncology therapies.

In addition to the highly anticipated PD-(L)1 x VEGF bispecific combination, the field of immuno-oncology is also rapidly advancing research into bispecific and multi-specific antibodies targeting PD-(L)1 along with other immune checkpoints such as CTLA-4, LAG3, and others. Combined targeting of CTLA-4 and PD-(L)1 can enhance T cell activity and persistence, while inhibition of LAG3 can further activate the exhaustion of T cells, overcoming tumor resistance to immunotherapy. Furthermore, dozens of new targets are continuously being explored, aiming to further improve the efficacy of existing immunotherapies across different tumor types and subgroups.

The research progress of these bispecific and multi-specific antibody studies is expected to significantly expand the applicability of immunotherapy, particularly for tumor subgroups that are currently insensitive to immunotherapy or patients who have developed resistance to single-targeted drugs. In the future, these innovative therapies may become complementary or even alternative to standard treatments, bringing new breakthroughs in tumor therapy. Chinese enterprises have significant potential in this field.

References:

BioNTech Completes Acquisition of Biotheus. BioNTech Press Release. 03 .02 .2025.

Herper, M. et al. Merck licenses Chinese cancer drug, searching for next Keytruda blockbuster. STAT. 14. 11. 2025.

Minghui Pharmaceutical Announces Promising Initial Results from Phase I Clinical Trial of MHB039A, a Novel PD-1 x VEGF Bispecific Antibody, in Patients with Relapsed/Refractory Solid Tumors. Biospace. 06. 11. 2024.

OncoC4 Announces FDA Clearance of IND Application for Potential Best-in-Class PD-1/VEGF Bispecific AI-081 in Advanced Solid Tumors. Globe Newswire. 02. 12. 2024.

Wang, C. et al. A Novel Bispecific Antibody CVL006 Superior to AK112 for Dual Targeting of PD-L1 and VEGF in Cancer Therapy. bioRxiv 2024.12.05.627108; doi: https://doi.org/10.1101/2024.12.05.627108

Pannu, A. PD-(L)1 x VEGF global competitive landscape. Sleuth. 20. 03. 2025.