Methods for achieving therapeutically effective doses of anti-CD47 agents for treating cancer
Methods are provided for treating a subject with a therapeutic dose of anti-CD47 agent by administering a primer agent prior to administering a therapeutically effective dose of an anti-CD47 agent to the subject.
1. A method of treating a mammalian subject with cancer with a therapeutic dose of an anti-CD47 agent that blocks the interaction between CD47 and SIRPα, selected from: an antibody that binds to CD47; an antibody that binds to SIRPα; a soluble SIRPα-binding CD47 fragment; and a soluble CD47-binding SIRPα fragment or a combination thereof, for treatment of the cancer, the method comprising:
(a) administering a sub-therapeutic dose of one of the anti-CD47 agents to the subject, wherein the sub-therapeutic dose is effective to increase production of reticulocytes; and
(b) administering a therapeutically effective dose of at least one of the anti-CD47 agents to the subject, wherein step (b) is performed in a range from about 3 days to about 21 days after beginning step (a).
2. The method according to claim 1 , wherein step (b) is performed in a range from about 6 days to about 8 days after beginning step (a).
3. The method according to claim 1 , further comprising after step (a) and prior to step (b): a step of determining whether administration of the sub-therapeutic dose was effective by detecting in a blood sample from the subject one or more of: an increase in the absolute or relative number of reticulocytes; an increase in the level of EPO; or a decrease in hemoglobin levels.
4. The method according to claim 3 , wherein the determining step comprises performing a reticulocyte count, wherein administration of the sub-therapeutic dose is determined to have been effective if the reticulocyte count is about 400×10 9 reticulocytes per liter (L) or more.
5. The method according to claim 3 , wherein the determining step is performed in a range from about 3 days to about 12 days after beginning step (a).
6. The method according to claim 1 , further comprising after step (a) and prior to step (b):
administering a second sub-therapeutic dose of one of the anti-CD47 agents to the subject wherein step (b) is performed in a range from about 3 days to about 21 days after administering the second sub-therapeutic dose.
7. The method according to claim 1 , wherein step (b) comprises administering the anti-CD47 agent in two or more doses of escalating concentration until a therapeutically effective dose is administered.
8. The method according to claim 1 , wherein step (b) comprises administering two or more therapeutically effective doses.
9. The method according to claim 1 , comprising administering in the therapeutic dose of (b) a combination of two or more anti-CD47 agents to the subject.
10. The method of claim 1 , wherein the mammalian subject is a human.
11. A method of treating a human subject with cancer with a therapeutic dose of an anti-CD47 antibody that blocks the interaction between CD47 and SIRPα for treatment of the cancer, the method comprising:
(a) administering a sub-therapeutic dose of the anti-CD47 antibody to the subject wherein the sub-therapeutic dose is sufficient to increase production of reticulocytes; and
(b) administering a therapeutically effective dose of the anti-CD47 antibody to the subject,
wherein step (b) is performed in a range from about 3 days to about 21 days after beginning step (a).
12. The method of claim 11 , wherein the sub-therapeutic dose is less than 10 mg/kg body weight.