Leland Stanford Junior University

Forty Seven, Inc.

Mark P Chao

Ravindra Majeti

Irving L Weissman

Siddhartha Jaiswal

Jens-Peter Volkmer

Jie Liu

Chris Hidemi Mizufune Takimoto

Arash Ash Alizadeh

Yinuo Cao

Kelly Tran

Roy Louis Maute

Keng Chi Li

Rachel Weissman-Tsukamoto

Methods are provided herein for determining and administering optimized dosing of therapeutic anti-D47 agents, in a schedule that provides safe escalation of dose while achieving a therapeutic level in a clinically effective period of time. The methods can comprise the steps of clearance, escalation, and maintenance. In one embodiment the dosing regimen administers an initial (i) sub-therapeutic dose of an anti-CD47 agent or (ii) a cytoreductive therapy to achieve a safe level of circulating tumor cells for subsequent treatment (clearance); escalating the dose of an anti-CD47 agent until a therapeutic dose is reached (escalation); and maintaining the therapeutic dose for a period of time sufficient to reduce tumor cells in the bone marrow of the patient (maintenance). In an alternative dosing regimen, a patient determined to have a safe level of circulating tumor cells at presentation is treated by the steps of escalation and maintenance without initial clearance.

Dosing parameters for CD47 targeting therapies to hematologic malignancies

Methods are provided herein for determining and administering optimized dosing of therapeutic anti-CD47 agents, in a schedule that provides safe escalation of dose while achieving a therapeutic level in a clinically effective period of time. The methods can comprise the steps of clearance, escalation, and maintenance. In one embodiment the dosing regimen administers an initial (i) sub-therapeutic dose of an anti-CD47 agent or (ii) a cytoreductive therapy to achieve a safe level of circulating tumor cells for subsequent treatment (clearance); escalating the dose of an anti-CD47 agent until a therapeutic dose is reached (escalation); and maintaining the therapeutic dose for a period of time sufficient to reduce tumor cells in the bone marrow of the patient (maintenance). In an alternative dosing regimen, a patient determined to have a safe level of circulating tumor cells at presentation is treated by the steps of escalation and maintenance without initial clearance.

Methods are provided to manipulate phagocytosis of cells, including hematopoietic cells, e.g. circulating hematopoietic cells, bone marrow cells, acute leukemia cells, etc.; and solid tumor cells. In some embodiments of the invention the circulating cells are hematopoietic stem cells, or hematopoietic progenitor cells, particularly in a transplantation context, where protection from phagocytosis is desirable. In other embodiments the circulating cells are leukemia cells, particularly acute myeloid leukemia (AML), where increased phagocytosis is desirable.

Methods for manipulating phagocytosis mediated by CD47

Methods, kits, and compositions are provided herein that can be used to treat CD20+ cancer using an anti-CD47 agent such as an antibody. The anti-CD47 agent can be used alone or in combination with one or more additional agent such as an anti-CD20 antibody.

Anti-CD47 agent-based treatment of CD20-positive cancer

Methods, kits, and compositions are provided herein that can be used to treat ovarian cancer using an anti-CD47 antibody. The anti-CD47 antibody can be used alone or in combination with one or more additional agent such as chemotherapy.

Anti-CD47 agent-based ovarian cancer therapy

Methods, kits, and compositions are provided herein that can be used to treat hematopoietic disorders using an anti-CD47 agent such as an antibody and a hypomethylating agent, such as azacitidine.

Combination therapies for treating myelodysplastic syndromes and acute myeloid leukemia

Markers of acute myeloid leukemia stem cells (AMLSC) are identified. The markers are differentially expressed in comparison with normal counterpart cells, and are useful as diagnostic and therapeutic targets.

Markers of acute myeloid leukemia stem cells

Methods are provided for treating a subject with an anti-CD47 agent.

Methods for determining and achieving therapeutically effective doses of anti-CD47 agents in treatment of cancer

Therapeutic and diagnostic methods are provided, which methods relate to the expression of calreticulin on cancer cells and hematopoietic cells.

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Mountain View, CA, United States of America

Mark P Chao