Leland Stanford Junior University

Forty Seven, Inc.

Ravindra Majeti

Irving L Weissman

Jie Liu

Mark P Chao

Jens-Peter Volkmer

Siddhartha Jaiswal

Stephen Willingham

Susan Sweeney Prohaska

Anne Kathrin Volkmer

Maureen C Howard

Emily Piccione Griffin

Maureen Howard

Catriona Helen Jamieson

Ronald Levy

Crystal L Mackall

Arash Ash Alizadeh

Chris Hidemi Mizufune Takimoto

Wan-Jen Hong

Robbie Majzner

Yinuo Cao

Kelly Tran

Rachel Weissman-Tsukamoto

Roy Louis Maute

Rebecca Richards

Antigen binding domain polypeptides (ABD) specific for human CD93 are provided, which ABD may be formatted as antibodies, as chimeric antigen receptors, and the like. T cells comprising an anti-CD93 CAR are useful in the treatment of cancer, e.g. hematologic malignancies.

Therapeutic antigen binding proteins specific for CD93 and methods of use thereof

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 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.

Methods for achieving therapeutically effective doses of anti-CD47 agents

Methods for treating myeloma by achieving therapeutically effective doses of anti-CD47 antibody

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

Humanized or chimeric anti-CD47 monoclonal antibodies are provided. The antibodies bind to and neutralize human CD47, and find use in various therapeutic methods. Preferred are non-activating antibodies. Embodiments of the invention include isolated antibodies and derivatives and fragments thereof, pharmaceutical formulations comprising one or more of the humanized or chimeric anti-CD47 monoclonal antibodies; and cell lines that produce these monoclonal antibodies. Also provided are amino acid sequences of the antibodies.

Humanized and chimeric monoclonal antibodies to CD47

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

Polypeptide compositions comprising a human immunoglobulin constant region with a modified IgG4 hinge region having an N-terminal deletion of 1, 2, 3, 4, 5 amino acids, relative to a native human IgG4 hinge sequence are provided. In some embodiments the hinge sequence further comprises the amino acid substitution S228P (Eu numbering). Polypeptides comprising the modified sequence optionally comprise a binding moiety specific for an epitope that is present on red blood cells; and can provide for reduced agglutination of hematopoietic cells compared to a comparable polypeptide with a native hinge region.

Modified immunoglobulin hinge regions to reduce hemagglutination

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

Growing community of inventors

Palo Alto, CA, United States of America

Ravindra Majeti