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|Ref Type||Journal Article|
|Authors||Knorr DA, Dahan R, Ravetch JV|
|Title||Toxicity of an Fc-engineered anti-CD40 antibody is abrogated by intratumoral injection and results in durable antitumor immunity.|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Date||2018 10 23|
|Abstract Text||Immune stimulation has emerged as a promising approach to the treatment of neoplastic diseases. Currently approved therapeutics, such as anti-CTLA4 and anti-PD1, are primarily aimed at blocking inhibitory signaling by immune cells. An alternative and potentially synergistic approach would involve activation of immune pathways by agonism of stimulatory receptors, such as CD40. Agonistic antibodies, while promising in principle, have encountered significant barriers in clinical trials limited by the systemic toxicity of such approaches. Using a mouse model humanized for both Fc receptors and CD40, we previously demonstrated enhanced antitumor activity with an Fc-modified antibody. We now demonstrate that this model recapitulates the platelet and hepatic toxicities seen with anti-CD40 antibodies in patients, providing a predictive measure of the dose-limiting activity of this approach. We further show that such toxicity can be circumvented and durable systemic antitumor immunity achieved by intratumoral delivery of an Fc-engineered anti-CD40 agonistic antibody.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|2141 V-11||2141 V11|2141-V11||CD40 Antibody 11||2141 V-11 is a human anti-CD40 antibody with modified Fc domain, which may induce durable anti-tumor immunity (PMID: 30297432).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||colorectal cancer||not applicable||2141 V-11||Preclinical - Cell line xenograft||Actionable||In a preclinical study, intratumoral injection of 2141 V-11 stimulated anti-tumor immune response, resulted in reduced tumor burden and prolonged survival in a cell line xenograft model of colorectal cancer (PMID: 30297432).||30297432|