John Paquet III BME 181 S01 08 April 2013

 2008 – 7.6 million deaths worldwide by cancer  13% of total worldwide deaths that year

 CD47- protein that coats surface of cells  “Don’t eat me” signal to immune cells  Cancer cells boost their CD47 levels  Macrophages ignore the cancer

 Blocking monoclonal anti-humanCD47 antibodies  Anti-hCD47 mAbs- include B6H12.2 and Bric126  Anti-hCD47 mAbs block CD47’s “don’t eat me” signal

 SIRPα on macrophages binds to CD47  Resulting signaling cascade inhibits phagocytosis  Anti-hCD47 mAb specifically binds to antigen CD47 to block “don’t eat me” signal  Cancer cells also output “eat me” signal- calreticulin  Disabling CD47 barrier exposes calreticulin “eat me” signal  Normal cells do not have calreticulin on surface, so macrophages don’t consume them

 In one mouse, human leukemic cancer was completely gone 1 day after single dose of antibody injected  In mice with human acute myelogenous leukemia, cancer was erased in a majority of the mice  Large tumors shrink, some smaller ones even vanish  Also successful at treating cancers that have already spread

 Anti-hCD47 mAbs prevent cancer from metastasizing  Greater the amount of CD47 expressed by cancer cells, the lesser the chance that subject survived ◦ Dosage can be increased  Effectiveness of antibody therapy was inversely proportional to initial tumor size

 Large doses of anti-hCD47 mAbs produce temporary amenia ◦ Red blood cell count recovers quickly  Not advisable after chemotherapy ◦ Normal cells are damaged due to high stress, so they have calreticulin on surface- “eat me” signal ◦ Disabling CD47 would enable phagocytosis of normal cells

 Can be grown in unlimited amounts  would likely be most effective when: ◦ tumor is maximally debulked ◦ used alongside antibodies that strengthen the “eat me” signals from surface proteins like calreticulin  Potential to treat nearly every type of cancer  $20 million grant from CIRM  Human trials to begin late 2013 or early 2014

 "Cancer." World Health Organization, Jan Web.  "Monoclonal Antibodies." Wikipedia. Wikimedia Foundation, 29 Mar Web.  "The CD47-signal Regulatory Protein Alpha (SIRPa) Interaction Is a Therapeutic Target for Human Solid Tumors." PubMed Central. National Academy of Sciences, 26 Mar Web.  Vaughan, Christopher. "Cancer Roundhouse: Evidence Mounts That a Single Antibody Could Knock out Many Cancers." Stanford Medicine, Summer Web.  Weiss, Jonathan. "Scientists Have Silver Bullet To Kill Multiple Cancers, Human Trials Starting." Medical Daily, 28 Mar Web.