In an effort to develop more effective cancer treatments scientists are looking for therapies that supercharge patients’ immune systems

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Schematic model of immune response induction using CD40-targeted Ag. Subcutaneous immunization with rAd-encoding SNP-CD40L fusion protein results in infection of proliferating and nonproliferating cells; thus, secreted gene products increase the Ag loads in vivo at the site of injection. The fusion protein then binds to CD40 on APCs via CD40L to initiate immune response induction and amplification. DCs can also be directly infected with rAd, leading to their maturation into professional APCs and subsequent secretion of the fusion protein into regional LNs to directly activate B cells. Thus, CD40L can act as an adjuvant and targeting molecule in both the peripheries and/or the secondary lymphoid organs. In the LNs, the CD40L-activated DCs activate Ag-specific CD8+ T cells to induce enhanced CTL activity and multiple cytokines producing cytotoxic T cells. Meanwhile, secreted CD40-targeted Ags activate B cells and elicit accelerated Ig isotype switch, early and persistent GC formation, and Th1-skewed Ab response.

In an effort to develop more effective cancer treatments, scientists are looking for therapies that supercharge patients’ immune systems.

One possibility is to use antibodies that activate CD40, an immune-cell protein that, when triggered, prompts the rest of immune system to spring into action.

Though promising, drugs that target CD40 have been limited by their significant side effects: at doses sufficient to kill tumors, the antibodies can be toxic.

CD40 molecule is a potential target for cancer immunotherapy.

There are number of completed and ongoing clinical trials where agonistic anti-CD40 monoclonal antibodies are employed to activate an anti-tumor T cell response via activation of dendritic cells.

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Cluster of differentiation 40, CD40 is a costimulatory protein found on antigen presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.

Deficiency can cause Hyper-IgM syndrome type 3.

Protein CD40 PDB 1CDF.png

Structure of protein CD40.Based on PyMOL rendering of PDB 1CDF.

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However, in a recent study, published in the Proceedings of the National Academy of Sciences, Rockefeller scientists David A. Knorr, Rony Dahan, and Jeffrey V. Ravetch describe a safer way to deliver this kind of treatment.

In previous studies, the team used a unique mouse model to engineer an antibody that binds tightly to human CD40 receptors.

This modified antibody, they found, eliminates tumors more effectively than any other drug in its class.

Using the same mouse model, the researchers have now found that their antibody can lead to blood and liver complications when delivered to the entire body at doses high enough to be effective.

To circumvent this issue, the researchers administered low doses of the drug directly to the tumor site.

This strategy controlled both the tumor injected, as well as tumors that were not injected—without causing the toxicities observed in past studies.

The researchers plan, with the support of the Robertson Therapeutic Development Fund, to begin clinical studies of the antibody this winter.

More information: David A. Knorr et al. Toxicity of an Fc-engineered anti-CD40 antibody is abrogated by intratumoral injection and results in durable antitumor immunity, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1810566115

Rony Dahan et al. Therapeutic Activity of Agonistic, Human Anti-CD40 Monoclonal Antibodies Requires Selective FcγR Engagement, Cancer Cell (2016). DOI: 10.1016/j.ccell.2016.05.001

Journal reference: Proceedings of the National Academy of Sciences Cancer Cell

Provided by: Rockefeller University

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