A novel bispecific antibody CVL006 superior to AK112 for dual targeting of PD-L1 and VEGF in cancer therapy

  1. Chunyan Wang
  2. Hao Huang
  3. Zeng Song
  4. Zhongyuan Li
  5. Jinwen Huang
  6. Liang Cao
  7. Ziai Wu
  8. Junfang Pan
  9. XiaoBing Chen
  10. Xiaokun Shen

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Abstract

Background

Preclinical and clinical studies highlight the enhanced anticancer efficacy of combining anti-VEGF/VEGFR drugs with immune checkpoint inhibitors (ICIs). PD-L1/VEGF bispecific antibodies outperform monotherapy or combined PD-L1 inhibitors and anti-VEGF antibodies by simultaneously blocking the PD-1/PD-L1 immune pathway and VEGF-driven angiogenesis, providing a dual mechanism for superior antitumor activity.

Methods

We developed CVL006, a novel bispecific antibody, by fusing an anti-PD-L1 VHH domain with a humanized IgG1 anti-VEGF monoclonal antibody. CVL006 retains antibody-dependent cellular cytotoxicity (ADCC) functionality. Preclinical evaluations included binding affinity and specificity assessments, dual-pathway blockade testing, and in vivo efficacy comparisons to atezolizumab and PD-1/VEGF bispecific antibody AK112 (ivonescimab).

Results

CVL006 demonstrated high affinity and specificity for human PD-L1 and VEGF. It effectively inhibited VEGF/VEGFR signaling and the PD-L1/PD-1 axis, suppressing VEGF-induced angiogenesis and reactivating T cells. This reactivation led to increased cytokine secretion critical for immune response. In vivo studies revealed CVL006’s superior antitumor efficacy, achieving greater tumor growth inhibition and angiogenesis suppression than atezolizumab. CVL006 also outperformed AK112 in preclinical models, showcasing robust antitumor activity.

Conclusions

CVL006 integrates immune checkpoint inhibition and tumor vascularization disruption, offering a comprehensive anticancer strategy. Its superior preclinical performance compared to atezolizumab and AK112 underscores its therapeutic potential, paving the way for further development and clinical translation.

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  1. Version published to 10.1093/abt/tbaf012
  2. PREreview

    This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at https://prereview.org/reviews/14837570.

    Does the introduction explain the objective of the research presented in the preprint? Yes The authors of the article were able to argue the importance of using bispecific antibodies in combination therapies as compared to monotherapies. Thus, they were able to explain their objective (To emphasize the unique features of CVL006) in the present context, bringing out the need to conduct the current study which was part of their innovative idea.
    Are the methods well-suited for this research? Somewhat appropriate Their methods are highly scientific and reproducible. On a positive sense the methods of data analysis also included multiple cancer models rather than just using one cancer model. However, we recommend to the authors to work on the clarity to break down some of the terminologies to be better understood even among those who are not specialist in the field. The manner of presentation also needs to be improved for coherence.
    Are the conclusions supported by the data? Somewhat supported Authors need to restructure statements made to make them concise. However, their conclusions statements provided specific understanding of the positive results achieved from the combined therapies which presented potential efficacy at reduced doses hence reducing chemotherapy-induced toxicity and improved patient tolerability.
    Are the data presentations, including visualizations, well-suited to represent the data? Highly appropriate and clear Authors used different presentation styles which provided clarification on their work and its highly commendable. Additionally, the color contract is good making them easily readable.
    How clearly do the authors discuss, explain, and interpret their findings and potential next steps for the research? Somewhat clearly The authors findings are not very concise and not easily understandable to "non-subject matter" people. However, they have identified clearly their study limitations and next steps in their concluding statement. Additionally, the authors should consider being uniformed in their referencing style.
    Is the preprint likely to advance academic knowledge? Highly likely The study unwinds a lot of academic insights in the manner in which it is conducted and provides a knowledge gap which serves as a fuel for the academic sector. Additionally, the study is providing new knowledge that combined therapy is more beneficial than monotherapy for cancer treatment.
    Would it benefit from language editing? Yes The study might benefit from language editing because of the previous issues raised on being concise and clear.
    Would you recommend this preprint to others? Yes, it's of high quality
    Is it ready for attention from an editor, publisher or broader audience? Yes, after minor changes

    Competing interests

    The authors declare that they have no competing interests.

  3. Version published to 10.1101/2024.12.05.627108v1 on bioRxiv