Leland Stanford Junior University

University of California

Systemix, Inc.

National Institutes of Health, a Component of the US Dept. of Health & Human Services

Forty Seven, Inc.

Stemcells California, Inc.

California Institute of Technology

The University of Tokyo

Other

Harvard College

Tufts University

Stemcells, Inc.

Irving L Weissman

Ravindra Majeti

Jens-Peter Volkmer

Kipp Andrew Weiskopf

Jie Liu

Aaron Michael Ring

Mark P Chao

Stephen Willingham

Siddhartha Jaiswal

Susan Sweeney Prohaska

Judith A Shizuru

Anne Kathrin Volkmer

Roy Louis Maute

Ann Tsukamoto

Koichi Akashi

Akanksha Chhabra

Joseph M McCune

Maureen C Howard

Nobuko Uchida

Laurie Elizabeth Ailles

Peter Schnorr

Yukoh Aihara

Charles M Baum

Kim J Hasenkrug

David W Buck

Catriona Helen M Jamieson

Cheryl A Stoddart

Melissa N McCracken

Kenan Christopher Garcia

Aashish Manglik

Andrew Curtis Kruse

Nicholas J Leeper

Tannishtha Reya

David Jeffrey Traver

Toshihiro Miyamoto

Sydney Gordon

Nan Guo Ring

Michael T Longaker

Aron M Levin

Piero D Dalerba

Agnieszka Czechowicz

Hiromitsu Nakauchi

Daniel Lewis Kraft

Hideki Masaki

David R Walt

Leroy E Hood

Stuart L Schreiber

Scott J Dylla

Michael F Clarke

Arash Ash Alizadeh

Divya Nag

Joseph C Wu

Roeland Nusse

Calvin Jay Kuo

Mark Lee

Doris Po Yi Ho

Kelly Marie McKenna

Charles K F Chan

Markus Gabriel Manz

Mingye Feng

Motoo Watanabe

Deepta Bhattacharya

Naoki Hosen

Motonari Kondo

Maureen Howard

Rahul Sinha

Yuval Rinkevich

Michael S McGrath

Jeffrey S Friedman

Howard K Gershenfeld

Diane Tseng

Benson M George

Gerlinde Wernig

Karl G Sylvester

Andrew Stephen Lee

Jonathan Tsai

Jun S Liu

Victor Albert Eng

Sharareh Gholamin

Chad Tang

Samuel Cheshier

Micha Drukker

Siddhartha S Mitra

Alexander D Boiko

Julien Sage

Keith S Chan

Richard Irving Sherwood

Amy Jo Wagers

Toshiyuki Yamane

Rachel Weissman-Tsukamoto

Daniel Mark Corey

Monika Tataria

Thanyaphong Na Nakorn

Nathaniel Fernhoff

Israel Biran

Jenny Tam

Ruth Tevlin

Anne Le

Hye Sook Kwon

Methods are provided for treating a subject with for an intracellular pathogen infection, by administering an agent that reduces the binding of CD47 on a infected cell to SIRPα on a host phagocytic cell, in an effective dose for increasing the phagocytosis of infected cells.

CD47 targeted therapies for the treatment of infectious disease

The present invention provides a clinically applicable method of stem cell transplantation that facilitates engraftment and reconstitutes immunocompetence of the recipient without requiring radiotherapy or chemotherapy, and without development of GVHD or graft rejection.

Non-genotoxic conditioning regimen for stem cell transplantation

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

The present invention provides a clinically applicable method of stem cell transplantation that facilitates engraftment and reconstitutes immunocompetence of the recipient without requiring radiotherapy or chemotherapy, and without development of GVHD or graft rejection. Aspects of the present invention are based on the discovery that the depletion of the endogenous stem cell niche facilitates efficient engraftment of stem cells into that niche. In particular, the present invention combines the use of selective ablation of endogenous stem cells with a combination of antibodies specific for CD117, and agents that modulate immunoregulatory signaling pathways, e.g. agonists of immune costimulatory molecules, in combination with the administration to the recipient of exogenous stem cells, resulting in efficient, long-term engraftment, even in immunocompetent recipients.

Engraftment of stem cells with a combination of an agent that targets stem cells and modulation of immunoregulatory signaling

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.

High affinity SIRP-α reagent are provided, which (i) comprise at least one amino acid change relative to the wild-type protein; and (ii) have an increased affinity for CD47 relative to the wild-type protein. Compositions and methods are provided for modulating phagocytosis in a mammal by administering a therapeutic dose of a pharmaceutical composition comprising a high affinity SIRPα reagent, which blocks the physiological binding interaction between SIRPα and its ligand CD47.

High affinity SIRP-alpha reagents and methods of using

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

In the methods of the invention, an agent that increases phagocytosis and/or efferocytosis of cellular components of coronary plaque is administered to the subject in a dose and for a period of time effective to stabilize, prevent or reduce aneurysm disease in the individual.

Targeting aneurysm disease by modulating phagocytosis pathways

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 are provided for targeting cells for depletion, including without limitation tumor cells, in a regimen comprising contacting the targeted cells with a combination of agents that modulate immunoregulatory signaling. Immunoregulatory modulating agents include (i) an agent that blockades CD47 activity; and (ii) an agent that agonizes an immune costimulatory molecule, e.g. CD137. The regimen may further comprise an agent that specifically binds to the target cell, e.g. an antibody or biologically active fragment or derivative thereof. The level of depletion of the targeted cell is enhanced relative to a regimen in which a single immunoregulatory modulating agent is used; and the effect may be synergistic relative to a regimen in which a single immunoregulatory modulating agent is used.

Enhanced depletion of targeted cells with CD47 blockade and an immune costimulatory agonist

Compositions and methods are provided for treating fibrosis in a mammal by administering a therapeutic dose of a pharmaceutical composition.

Antifibrotic activity of CD47 blockade in the liver

The present invention provides a clinically applicable method of stem cell transplantation that facilitates engraftment and reconstitutes immunocompetence of the recipient without requiring radiotherapy or chemotherapy, and without development of GVHD or graft rejection. Aspects of the present invention are based on the discovery that the depletion of the endogenous stem cell niche facilitates efficient engraftment of stem cells into that niche. In particular, the present invention combines the use of selective ablation of endogenous stem cells, in combination with the administration to the recipient of exogenous stem cells, resulting in efficient, long-term engraftment and tolerance.

Selective immunodepletion of endogenous stem cell niche for engraftment

Growing community of inventors

Stanford, CA, United States of America

Irving L Weissman