Leland Stanford Junior University

Ab Initio Biotherapeutics, Inc.

The United States of America, As Represented by the Secretary, Department of Health and Human Services

Forty Seven, Inc.

Vib Vzw

Vrije Universiteit Brussel

Aaron Michael Ring

Irving L Weissman

Kipp Andrew Weiskopf

Aashish Manglik

Andrew Curtis Kruse

Roy Louis Maute

Kenan Christopher Garcia

Aron M Levin

Jens-Peter Volkmer

Melissa N McCracken

Warren Jaye Leonard

Sydney Gordon

Nan Guo Ring

Suman Mitra

Christopher K Garcia

Brian K Kobilka

Judith A Shizuru

Akanksha Chhabra

Peter Schnorr

Kenneth S Lin

Jie Liu

Jan Steyaert

Els Pardon

K Christopher Garcia

Benson M George

Daniel Mark Corey

Chia Chi Ho

Aasish Manglik

Brian Kobilka

Weissman Irving L L

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

Novel human interleukin-2 (IL-2) muteins or variants thereof are provided. In particular, provided are IL-2 muteins that have an increased binding capacity for IL-2Rβ receptor and a decreased binding capacity for IL-2Rγreceptor, as compared to wild-type IL-2. Such IL-2 muteins are useful, for example, as IL-2 partial agonist and antagonists in applications where reduction or inhibition of one or more IL-2 and/or IL-15 functions is useful (e.g., in the treatment of graft versus host disease (GVHD) and adult T cell leukemia). Also provided are nucleic acids encoding such IL-2 muteins, methods of making such IL-2 muteins, pharmaceutical compositions that include such IL-2 muteins and methods of treatment using such pharmaceutical compositions.

Superagonists, partial agonists and antagonists of interleukin-2

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

Novel human interleukin-2 (IL-2) muteins or variants thereof, and nucleic acid molecules and variants thereof are provided. Methods for producing these muteins as well as methods for stimulating the immune system of an animal are also disclosed. In addition, the invention provides recombinant expression vectors comprising the nucleic acid molecules of this invention and host cells into which expression vectors have been introduced. Pharmaceutical compositions are included comprising a therapeutically effective amount of a human IL-2 mutein of the invention and a pharmaceutically acceptable carrier. The IL-2 muteins can be used in pharmaceutical compositions for use in treatment of cancer and in stimulating the immune response.

Superagonists and antagonists of interleukin-2

High affinity PD-1 mimic polypeptides are provided, which (i) comprise at least one amino acid change relative to a wild-type PD-1 protein; and (ii) have an increased affinity for PD-L1 relative to the wild-type protein. Compositions and methods are provided for modulating the activity of immune cells in a mammal by administering a therapeutic dose of a pharmaceutical composition comprising a high affinity PD-1 mimic polypeptide, which blocks the physiological binding interaction between PD-1 and its ligand PD-L1 and/or PD-L2.

High affinity PD-1 agents and methods of use

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 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

Provided herein are SIRP-gamma, SIRP-beta or SIRP-beta2 decoy polypeptides for immunotherapy and/or treatment of cancer, anemia, transplant, asthma, allergy, auto-immune disease, and viral infection.

SIRP-gamma polypeptide compositions and treatment of cancer

Novel human interleukin-2 (IL-2) muteins or variants thereof are provided. In particular, provided are IL-2 muteins that have an increased binding capacity for IL-2R&#x3b2; receptor and a decreased binding capacity for IL-2R&#x3b3;receptor, as compared to wild-type IL-2. Such IL-2 muteins are useful, for example, as IL-2 partial agonist and antagonists in applications where reduction or inhibition of one or more IL-2 and/or IL-15 functions is useful (e.g., in the treatment of graft versus host disease (GVHD) and adult T cell leukemia). Also provided are nucleic acids encoding such IL-2 muteins, methods of making such IL-2 muteins, pharmaceutical compositions that include such IL-2 muteins and methods of treatment using such pharmaceutical compositions.

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.

Provided herein are several methods for selecting agents that bind to transmembrane receptors in a conformationally-selective way. In some embodiments, the method may comprise producing: a transmembrane receptor in an active conformation; and said transmembrane receptor in an inactive conformation and using cell sorting to select, from a population of cells comprising a library of cell surface-tethered extracellular capture agents, cells that are specifically bound to either the transmembrane receptor in its active conformation or the transmembrane receptor in its inactive conformation, but not both. In other embodiments, the method may comprise: contacting a GPCR with a population of cells that comprise a library of surface-tethered extracellular proteins; labeling the cell population with a conformationally-specific binding agent, e.g., a G-protein or mimetic thereof; and using cell sorting to select from the cell population cells that bind to the agent.

Compositions comprising G protein-coupled receptors maintained in a conformationally selective manner by a modulator

Cell loss by apoptosis is a common feature in certain conditions, including cancer. Dying tumor cells induce immune tolerance within the tumor microenvironment largely through highly conserved homeostatic clearance programs that are designed to restore tissue homeostasis and contribute to the formation of an immunosuppressive niche. The translocation of phosphatidylserine (PS) on cellular membranes, during the initial phases of apoptosis, functions as a recognition and removal signal that limits the immunogenicity of cell death. To remove inhibitory signals in the homeostatic clearance pathway a fusion protein comprising a phosphatidylserine binding domain and an immunostimulatory domain can restore immune responses to dead tumor cells in antigen cross presentation assays and promotes recruitment and retention of tumor antigen specific immune effector cells into tumors. These effects combine to elicit anti-tumor immunity, improve responses to immune checkpoint inhibitors, and enhance the effectiveness of adoptive T cell transfers using engineered T cells.

Growing community of inventors

New Haven, CT, United States of America

Aaron Michael Ring