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Updated: Jun 4, 2025
Targeted Antibody Blocking by a Dual-Functional Conjugate of Antigenic Peptide and Fc-III Mimetics DCAF
Published on: September 17, 2019
An antibody cocktail targeting two different CD73 epitopes enhances enzyme inhibition and tumor control
Jin-Gen Xu1,2, Shi Chen2, Yang He3
1Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Scienes, Guangzhou, China.
Abstract:
CD73, an ectoenzyme responsible for adenosine production, is often elevated in immuno-suppressive tumor environments. Inhibition of CD73 activity holds great promise as a therapeutic strategy for CD73-expressing cancers. In this study, we have developed a therapeutic anti-human CD73 antibody cocktail, HB0045. HB0045 is a 1:1 mixture of two humanized monoclonal IgG1 antibodies (mAbs), HB0038 and HB0039. The cocktail not only harnesses the advantages of its parental mAbs in enzyme inhibition but also shows a significantly greater capability of promoting T cell proliferation in vitro. Structural analyses show that HB0045 effectively locks the CD73 dimer in a "partially open" non-active conformation through a double lock mechanism. In various animal models of syngeneic and xenograft tumors, HB0045 inhibits tumor growth more potently than the single mAbs. Collectively, our findings provide functional and structural insights into the mechanism of a CD73-targeting antibody cocktail.
Insights
A new antibody cocktail, HB0045, targets CD73 (an enzyme in immunosuppressive tumors) to inhibit cancer growth. This cocktail enhances T cell proliferation and shows superior tumor inhibition compared to single antibodies.
Area of Science:
- Immunology
- Oncology
- Structural Biology
Background:
- CD73 ectoenzyme elevates adenosine in immunosuppressive tumor microenvironments.
- CD73 inhibition is a promising therapeutic strategy for CD73-expressing cancers.
Purpose of the Study:
- To develop and characterize a novel therapeutic anti-human CD73 antibody cocktail, HB0045.
- To investigate the mechanism of action and in vivo efficacy of HB0045.
Main Methods:
- Development of a 1:1 mixture of two humanized monoclonal IgG1 antibodies (HB0038 and HB0039) forming the HB0045 cocktail.
- In vitro assessment of T cell proliferation.
- Structural analysis of HB0045 binding to CD73.
- In vivo evaluation of HB0045 efficacy in syngeneic and xenograft tumor models.
Main Results:
- HB0045 demonstrated enhanced T cell proliferation promotion compared to single parental antibodies.
- Structural analysis revealed HB0045 locks CD73 dimers in a non-active conformation via a double lock mechanism.
- HB0045 exhibited more potent inhibition of tumor growth in vivo than individual antibodies.
Conclusions:
- The CD73 antibody cocktail HB0045 offers a potent therapeutic strategy for CD73-expressing cancers.
- HB0045's mechanism involves locking CD73 dimers, enhancing T cell responses, and inhibiting tumor growth.
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