Leland Stanford Junior University

Forty Seven, Inc.

Jens-Peter Volkmer

Irving L Weissman

Jie Liu

Ravindra Majeti

Stephen Willingham

Susan Sweeney Prohaska

Anne Kathrin Volkmer

Mark P Chao

Maureen C Howard

Aaron Michael Ring

Kipp Andrew Weiskopf

Piero D Dalerba

Nan Guo Ring

Doris Po Yi Ho

Kelly Marie McKenna

Mingye Feng

Maureen Howard

Chris Hidemi Mizufune Takimoto

Diane Tseng

Benson M George

Mark Ping Chao

Anne K Volkmer

Therapeutic and diagnostic methods are provided, which methods relate to the induction of expression of calreticulin on phagocytic cells. Specifically, the methods relate to macrophage-mediated programmed cell removal (PrCR), the methods comprising increasing PrCR by contacting a phagocytic cell with a toll-like receptor (TLR) agonist; or down-regulating PrCR by contacting a phagocytic cell with an inhibitor of Bruton's tyrosine kinase (BTK). In some embodiments, an activator of TLR signaling or a BTK agonist is provided in combination with CD47 blockade.

Use of TLR agonist and anti-CD47 agent to enhance phagocytosis of cancer cells

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 for targeting cells for depletion, including, without limitation, cancer cells, in a regimen comprising contacting the targeted cells with a combination of agents, including (i) an agent that blockades CD47 activity; and (ii) an antibody that specifically binds to EGFR. In some embodiments the cancer cells have a mutated form of one or more of KRAS, NRAS and BRAF. The level of depletion of the targeted cell is enhanced relative to a regimen in which a single agent is used; and the effect may be synergistic relative to a regimen in which a single agent is used.

Treatment of cancer with dual targeting of CD47 and EGFR

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

Therapeutic and diagnostic methods are provided, which methods relate to the induction of expression of calreticulin on phagocytic cells. Specifically, the methods relate to macrophage-mediated programmed cell removal (PrCR), the methods comprising increasing PrCR by contacting a phagocytic cell with a toll-like receptor (TLR) agonist; or down-regulating PrCR by contacting a phagocytic cell with an inhibitor of Bruton's tyrosine kinase (BTK). In some embodiments, an activator of TLR signaling or a BTK agonist is provided in combination with CD4 7 blockade.

Anti-SIRP&#x3b1; antibodies, including multi-specific anti-SIRP&#x3b1; antibodies, are provided, as are related compositions and methods. The antibodies of the disclosure bind to SIRP&#x3b1; and can block the interaction of CD47 on one cell with SIRP&#x3b1; on a phagocytic cell.

Anti-SIRP-alpha antibodies and related methods

Anti-SIRP&#x3b1; antibodies, including multi-specific anti-SIRP&#x3b1; antibodies, are provided, as are related compositions and methods. The antibodies of the disclosure bind to SIRP&#x3b1; and can block the interaction of CD47 on one cell with SIRP&#x3b1; on a phagocytic cell. The subject anti-SIRP&#x3b1; antibodies find use in various therapeutic methods. Embodiments of the disclosure include isolated antibodies and derivatives and fragments thereof, pharmaceutical formulations comprising one or more of the anti-SIRP&#x3b1; antibodies; and cell lines that produce the antibodies. Also provided are amino acid sequences of exemplary anti-SIRP&#x3b1; antibodies.

Disrupting FC receptor engagement on macrophages enhances efficacy of anti-SIRPalpha antibody therapy

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

Growing community of inventors

Menlo Park, CA, United States of America

Jens-Peter Volkmer