July 23, 2024

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Fc-optimized CD40 agonistic antibody can induce anti-tumor response

Science: Fc-optimized CD40 agonistic antibody can induce sustained anti-tumor response


Fc-optimized CD40 agonistic antibody can induce anti-tumor response. 


According to the latest global cancer burden data released by the World Health Organization’s Agency for Cancer Research (IARC) in 2020, bladder cancer is the tenth cancer with the number of new cases.

In 2020, there are an estimated 570,000 new cases of prostate cancer worldwide, most of which Men, accounting for 77%.


Fc-optimized CD40 agonistic antibody can induce anti-tumor response
The top ten cancer types with the number of new cancer cases in 2020, source: WHO



Most patients present with early non-muscular invasive bladder cancer (NMIBC). The current treatment strategy is to remove first and then BCG treatment.

BCG treatment is to use live vaccines made of attenuated Mycobacterium bovis suspension for bladder perfusion, which can enhance the activity of macrophages and activate T lymphocytes. By enhancing the body’s cellular immune function to cause anti-tumor response.

However, up to 75% of patients do not respond to BCG treatment, and even if they do, there is a risk of recurrence and deterioration. Therefore, there is an urgent need to develop new therapies.


Recombinant human immunoglobulin G (IgG) antibodies can enhance the anti-tumor immune response.

The stimulatory receptor CD40 plays a central role in the development of anti-tumor immunity and tumor-specific T cell responses.

The accumulation of CD40 in the human bladder tumor microenvironment provides a theoretical basis for specifically targeting the CD40 pathway in non-muscular invasive bladder cancer (NMIBC).


On May 19, 2021, the Rockefeller University research team published a research paper titled: Dendritic cell targeting with Fc-enhanced CD40 antibody agonists induces durable antitumor immunity in humanized mouse models of bladder cancer in Science Translational Medicine journal.


The study found that the dendritic cells of bladder cancer highly express CD40, and the delivery of Fc-optimized CD40 agonistic antibodies into the bladder of tumor mouse models can promote the anti-bladder tumor response, indicating that this therapy has the potential to replace BCG in clinical bladder cancer treatment.


Fc-optimized CD40 agonistic antibody can induce anti-tumor response



As we all know, antibodies are composed of an antigen binding site (Fab) and a crystallizable site (Fc).

The Fab segment can recognize free molecular targets and receptors on the cell surface, and determine the specific recognition of the antibody to cancer cells.

The Fc segment determines the effector function of the antibody, including antibody-dependent cytotoxicity (ADCC) and complement dependence.

Cytotoxicity (CDC). By optimizing and enhancing the Fc segment, the effector function of therapeutic antibodies can be improved.



Fc-optimized CD40 agonistic antibody can induce anti-tumor response



First, the research team used an orthotopic mouse model of bladder cancer to describe the tumor microenvironment and found that dendritic cells highly express CD40, indicating that CD40 plays an important role in bladder cancer tumors.


The research team tried to use CD40 antibodies to antagonize CD40 in mouse tumors. Compared with BCG treatment, CD40 antibody resulted in a significant reduction in bladder tumors.


CD40 antagonism can cause CD8+ T cell-dependent anti-tumor responses.

Therefore, the research team used CD8 antibodies to deplete CD8+ T cells in mice and found that the anti-tumor effects of CD40 antibodies were greatly limited.




After proving the biological principle of using mouse anti-CD40 antibodies for CD40 immunization in the bladder, the research team studied the anti-tumor therapeutic potential of fully human anti-CD40 antibodies in a syngeneic and species-matched in vivo environment related to clinical transformation .

The research team used a fully human Fc-optimized anti-CD40 antibody to conduct experiments and found that its antagonism to CD40 in tumors induced humanized cells to produce powerful anti-tumor immunity.





The first-generation CD40 antibody has not been promoted due to its systemic toxicity.

The research team evaluated the durability and side effects of human-derived Fc-optimized CD40 antibody and found that compared with BCG treatment, the intravesical delivery of human-derived Fc-optimized CD40 antibody was greatly reduced The tumor volume has been decreasing continuously, and the mice did not show toxicity, indicating that the antibody has a good prospect for clinical application.



In summary, this study provides supporting evidence for the clinical transformation of bladder cancer treatment with CD40 agonistic antibodies, and identifies an important mechanism by which CD40 drives the immune response of bladder cancer.





Science: Fc-optimized CD40 agonistic antibody can induce sustained anti-tumor response

(source:internet, reference only)

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