Next-IO™ Ang-2 & VEGF Therapeutic Bispecific Antibody Program

About This Program

This program aims to develop Ang-2 & VEGF therapeutic bispecific antibody for immuno-oncology.

Angiogenesis, VEGF, angiopoietin (Ang) 1, and Ang2, are the factors regulating tumor angiogenesis. Inhibition of the VEGF pathway is known to have good anti-tumor effects in many tumors. But efficacy is not universal. In some cases, such as brain tumors, this pathway fails to improve overall survival.

Studies have shown that combining Ang-2 with VEGF may have strong vascular changes. The bispecific antibody, Ang-2 & VEGF, can also be used in combination with chemotherapy or radiation therapy. In conclusion, the combination of anti-Ang-2 / VEGF-A proposes a new outlook to next-generation combination therapy strategy.

Ang-2 & VEGF

VEGF is a key driver in germination angiogenesis and is known to be overexpressed in most solid cancers. Angiogenesis has been characterized as a fundamental process of tumor cell proliferation and viability, which has led to the development of pharmacological agents for anti-angiogenesis to disrupt vascular supply and starve tumors of nutrients and oxygen, primarily by blocking VEGF/VEGF receptor signaling.

Ang-2 participates in the resistant pathway of anti-VEGF therapy in the preclinical model of Glioblastoma (GBM). Ang-2 binds to the TEK receptor tyrosine kinase (Tie-2) receptor. And in the physiological setting, Ang-2 inhibits Tie-2 signaling, destabilizes blood vessels and promotes VEGF-induced angiogenesis. Ang-2 mediates Tie-2⁺ macrophage homing to human GBMs. In TME, the macrophage population is then reprogrammed into a promo, proangiogenic phenotype, in an Ang-2 dependent manner.

Fig.1 Differential Effects of Ang-2/VEGF-A Inhibiting Antibodies in Combination with Radiotherapy or Chemotherapy.¹

Ang-2 & VEGF in Cancer Studies

Here are some published data about Ang-2 & VEGF working as a potential target for cancer immunotherapy.

• Ang-2/VEGF Inhibition (A2V) delays tumor growth and prolongs survival in two subtypes of human glioblastoma stem cell lines, compared with monotherapy with anti- Ang-2 (LC06) and VEGF (B20), respectively.

Fig.2 Treatment with A2V prolongs survival and delays tumor growth in the orthotopic Gl261 and the MGG8 models.³

• Dual angiopoietin-2 and VEGFA inhibition elicits anti-tumor immunity.

Fig.3 Individual volumes and Kaplan-Meier survival curves of orthotopic MMTV-PyMT tumors treated as indicated.²

• Anti-tumor immunity by dual angiopoietin-2 and VEGFA inhibition is achieved by PD-1 checkpoint blockade.

Fig.4 Growth of individual tumors. Arrows indicate start of treatment.²

Ongoing Clinical Trials

• Currently, only one Ang-2 & VEGF therapeutic bispecific antibody is evaluated in a clinical phase II trial.
• In this case, Ang-2 & VEGF is still a compelling combination for cancer immunotherapy. In an effort to optimally leverage Ang-2 & VEGF-mediated immune response, our next generation of Ang-2 & VEGF targeting treatment attempts to explore combination therapy trials by involving other immunomodulatory agents.

Program Planning and Management

We have extensive knowledge of end-to-end program development. For each program, we are committed to delivering the final complete program to our clients within 1.5 years before entering the IND stage.

Fig.5 Project pipeline management of therapeutic monoclonal antibody.

Cooperation

Creative Biolabs is looking for potential partners (include but not limit to major pharma or biotech firms) to develop Ang-2 & VEGF Therapeutic Bispecific antibody program together. Our scientists are dedicated to bringing years of valuable experience to our partner and achieve a meaningful partnership. For any partners interest in our Next-IO™ programs, Creative Biolabs welcomes collaboration.

Here are two ways for your choice, and please contact us for more details.

1) Collaborate with us and co-develop the programs from the discovery phase to IND enabling. Costs will be shared.

2) Become a licensed candidate for our programs.

With our quality control protocol and knowledge of global regulatory requirements, we can help our partners advance their programs with more chance to succeed. Look forward to cooperating with you in the near future.

References

• Gergely, Solecki.; et al. Differential Effects of Ang-2/VEGF-A Inhibiting Antibodies in Combination with Radio- or Chemotherapy in Glioma. Cancers. 2019, 11(3):314.
• Schmittnaegel.; et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Science Translational Medicine. 2017, 9(385): eaak9670.
• Kloepper, J.; et al. Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proceedings of the National Academy of Sciences. 2016, 113(16):4476-4481.