Source Paper
Stephen B. Willingham, Jens-Peter Volkmer, Andrew J. Gentles, Debashis Sahoo, Piero Dalerba et al.
Proceedings of the National Academy of Sciences • 2012
CD47, a “don't eat me” signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.
Objective: To validate the safety and efficacy of anti-CD47 antibody targeting in an orthotopic mouse breast cancer model using immune competent hosts
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Implant mouse breast cancer cells orthotopically into immune competent mice to establish tumors
Note: Model uses immune competent hosts rather than immunodeficient mice
“The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model”
Treat tumor-bearing mice with anti-CD47 monoclonal antibodies to block CD47 signaling
Note: Treatment can be initiated at different tumor sizes with varying outcomes
“Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative”
Track tumor growth inhibition and measure mouse survival over time following anti-CD47 antibody administration
Note: Survival increased over time with treatment
“Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time”
Evaluate whether anti-CD47 antibody therapy prevents metastasis formation or treats existing metastatic disease
Note: Therapy initiated on larger tumors showed ability to prevent or treat metastasis
“Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis”
Immune competent hosts used for orthotopic breast cancer model