Leland Stanford Junior University

University of California

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

Kipp Andrew Weiskopf

Irving L Weissman

Aaron Michael Ring

Joseph M McCune

Judith A Shizuru

Akanksha Chhabra

Kim J Hasenkrug

Peter Schnorr

Cheryl A Stoddart

Kenan Christopher Garcia

Jens-Peter Volkmer

Roy Louis Maute

Aron M Levin

Nan Guo Ring

Stephen Willingham

Diane Tseng

Julien Sage

Chia Chi Ho

Joseph M Mccune

Weissman Irving L L

CherylA Stoddart

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. 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

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 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

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 SIRP&#x3b1; on a host phagocytic cell, in an effective dose for increasing the phagocytosis of infected cells.

Methods and compositions are provided for inducing phagocytosis of a target cell, treating an individual having cancer, treating an individual having an intracellular pathogen infection (e.g., a chronic infection), and/or reducing the number of inflicted cells (e.g., cancer cells, cells infected with an intracellular pathogen, etc.) in an individual. Methods and compositions are also provided for predicting whether an individual is resistant (or susceptible) to treatment with an anti-CD47/SIRPA agent. In some cases, the subject methods and compositions include an anti-MHC Class I/LILRB1 agent. In some cases, the subject methods and compositions include an anti-MHC Class I/LILRB1 agent and an anti-CD47/SIRPA agent (e.g., co-administration of an anti-MHC Class I/LILRB1 agent and an anti-CD47/SIRPA agent). Kits are also provided for practicing the methods of the disclosure.

Compositions and methods for inducing phagocytosis of MHC class I positive cells and countering anti-CD47/SIRPA resistance

High affinity SIRP-&#x3b1; 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 SIRP&#x3b1; reagent, which blocks the physiological binding interaction between SIRP&#x3b1; and its ligand CD47.

Methods are provided for enhancing immunization strategies by manipulation, e.g. in vitro manipulation, of phagocytic antigen presenting cells. In the methods of the invention, phagocytic antigen presenting cells (phAPC) are incubated with a particulate antigen in the presence of an anti-CD47 agent in a dose and for a period of time sufficient to allow the phAPC to phagocytose the particulate antigen, which process generates a 'loaded' phAPC. The loaded phAPC is contacted with a population of T cells matched for at least one major histocompatibility locus with the phAPC, where the T cells are stimulated after contacting to generate an effector response against an epitope or epitopes present on the particulate antigen.

Use of anti-CD47 agents to enhance immunization

Methods are provided for treatment of lung cancers, particularly small cell lung cancer with targeted therapy, which optionally includes an agent that selectively blocks CD47 binding to SIRP&#x3b1;.

Targeted therapy for small cell lung cancer

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. Antibodies that are bispecific for SIRP&#x3b1; and a second antigen are termed Bi-specific Macrophage Enhancing (BiME) antibodies and have emergent properties. 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.

Growing community of inventors

Brookline, MA, United States of America

Kipp Andrew Weiskopf