Abstract: High affinity SIRP-? 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? reagent, which blocks the physiological binding interaction between SIRP? and its ligand CD47.

Abstract: Methods, compositions and kits for producing functional chondrocytes, skeletal cells, bone marrow stromal cells, and progenitor cells thereof are provided. These methods, compositions and kits find use in producing chondrocytes, osteoblasts, stromal cells, and progenitor cells thereof in vivo, or in vitro for transplantation, for experimental evaluation, as a source of lineage- and cell-specific products, and the like, for example for use in treating human disorders of the cartilage, bone and hematopoietic system. In some embodiments, specific combinations of protein factors are identified for reprogramming non-skeletal cells into bones, hematopoietic stroma, and chondrocytes, which may be provided in vitro or in vivo.

Abstract: 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.

Abstract: 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.

Abstract: 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.

Abstract: 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.

Abstract: 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 or 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.

Abstract: 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?.

Abstract: 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.

Abstract: 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.

Abstract: 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.

Abstract: Methods, compositions and kits for producing functional chondrocytes, skeletal cells, bone marrow stromal cells, and progenitor cells thereof are provided. These methods, compositions and kits find use in producing chondrocytes, osteoblasts, stromal cells, and progenitor cells thereof in vivo, or in vitro for transplantation, for experimental evaluation, as a source of lineage- and cell-specific products, and the like, for example for use in treating human disorders of the cartilage, bone and hematopoietic system. In some embodiments, specific combinations of protein factors are identified for reprogramming non-skeletal cells into bones, hematopoietic stroma, and chondrocytes, which may be provided in vitro or in vivo.

Abstract: 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.

Abstract: Methods are provided for targeting pediatric brain tumor cells for depletion.

Abstract: 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 immunoregulatory agents. 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.

Abstract: 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.

Abstract: Methods are provided for treatment of hematologic cancers, particularly lymphomas and leukemias, including without limitation myelogenous and lymphocytic leukemias. A combination of antibodies specific for CD47; and specific for a cancer associated cell surface marker are administered to the patient, and provide for a synergistic decrease in cancer cell burden. The combination of antibodies may comprise a plurality of monospecific antibodies, or a bispecific or multispecific antibody. Markers of interest include without limitation, CD20, CD22, CD52, CD33; CD96; CD44; CD123; CD97; CD99; PTHR2; and HAVCR2.

Abstract: Methods and compositions are provided for inducing phagocytosis of a target cell in an individual, by blocking the interaction between CD24 on a target cell and Siglec10 on a phagocytic cell.

Abstract: 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?.

Abstract: 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.