John Paquet IIIBME 181 S0108 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

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"Monoclonal Antibodies." Wikipedia. Wikimedia Foundation, 29 Mar. 2013. Web. <http://en.wikipedia.org/wiki/Monoclonal_antibodies>

"The CD47-signal Regulatory Protein Alpha (SIRPa) Interaction Is a Therapeutic Target for Human Solid Tumors." PubMed Central. National Academy of Sciences, 26 Mar. 2012. Web. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3340046/>

Vaughan, Christopher. "Cancer Roundhouse: Evidence Mounts That a Single Antibody Could Knock out Many Cancers." Stanford Medicine, Summer 2012. Web. <http://stanmed.stanford.edu/2012summer/article7.html>

Weiss, Jonathan. "Scientists Have Silver Bullet To Kill Multiple Cancers, Human Trials Starting." Medical Daily, 28 Mar. 2013. Web. <http://www.medicaldaily.com/articles/14434/20130328/cancer-treatment-cd47-miracle-bullet-breast-colon-bladder-antibody-eat-macrophage-immune.htm>