Abstract: The invention provides co-administration regimes of immunotherapeutic agents specifically binding to c-kit or inhibiting CD47-SIRP? for ablation of endogenous HSPCs. Relatively low levels of anti-c-kit result in saturation of binding to c-kit on HSPCs without significant reduction of the levels HSPCs. Significant reduction of the level of HSPCs can be obtained when the action of anti-c-kit is promoted by an immunotherapeutic agent inhibiting CD47-SIRP?. HSPCs expressing c-kit can thus be reduced to an acceptable level an acceptable level to permit introduction of replacement HSPCs without detrimental delay during which a subject has inadequate HSPCs.

Abstract: 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? on a host phagocytic cell, in an effective dose for increasing the phagocytosis of infected cells.

Abstract: 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.

Abstract: 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.

Abstract: Methods are provided for the generation of mesodermal cell types and derivatives thereof. Also provided are methods for generating purified populations of mesodermal cell types and derivatives thereof. The instant disclosure also provides methods of screening for cellular responses of the generated mesodermal cell types and derivatives thereof. Also provide are methods for screening for organismal phenotypes induced by introduction of the generated mesodermal cell types and derivatives thereof. Treatment methods making use of the generated mesodermal cell types and derivatives thereof are also provided. The instant disclosure also provides systems, compositions, and kits for practicing the methods of the disclosure.

Abstract: 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.

Abstract: Anti-SIRP? antibodies, including multi-specific anti-SIRP? antibodies, are provided, as are related compositions and methods. The antibodies of the disclosure bind to SIRP? and can block the interaction of CD47 on one cell with SIRP? on a phagocytic cell. Antibodies that are bispecific for SIRP? and a second antigen are termed Bi-specific Macrophage Enhancing (BiME) antibodies and have emergent properties. The subject anti-SIRP? 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? antibodies; and cell lines that produce the antibodies. Also provided are amino acid sequences of exemplary anti-SIRP? antibodies.

Abstract: Anti-SIRP? antibodies, including multi-specific anti-SIRP? antibodies, are provided, as are related compositions and methods. The antibodies of the disclosure bind to SIRP? and can block the interaction of CD47 on one cell with SIRP? on a phagocytic cell. The subject anti-SIRP? 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? antibodies; and cell lines that produce the antibodies. Also provided are amino acid sequences of exemplary anti-SIRP? antibodies.

Abstract: 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? on a host phagocytic cell, in an effective dose for increasing the phagocytosis of infected cells.

Abstract: 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.

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: 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 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 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: 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.

Abstract: Compositions and methods are provided relating to anti-SIRP? agonist antibodies. The antibodies of the invention bind to human SIRP?, and activate signaling, thereby inhibiting processes mediated by SIRP?, including without limitation phagocytosis. Embodiments of the invention include isolated antibodies and derivatives and fragments thereof, pharmaceutical formulations comprising one or more of the anti-SIRP? agonist antibodies; and cell lines that produce these antibodies.

Abstract: Anti-SIRP? antibodies, including multi-specific anti-SIRP? antibodies, are provided, as are related compositions and methods. The antibodies of the disclosure bind to SIRP? and can block the interaction of CD47 on one cell with SIRP? on a phagocytic cell. The subject anti-SIRP? 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? antibodies; and cell lines that produce the antibodies. Also provided are amino acid sequences of exemplary anti-SIRP? antibodies.

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: Methods and compositions are provided for regenerating smooth muscle tissue by the provision of a purified population of epicardial-derived pericytes, where the smooth muscle tissue may comprise, without limitation, coronary artery tissue; kidney tissue, etc. Compositions and kits for practicing the methods and/or for use with the systems of the disclosure are also provided.

Abstract: Methods and compositions are provided for the therapeutic use of hedgehog agents, for enhancing bone growth and regeneration in diabetic or pre-diabetic patients, including repair following injury, osseointegration of implants, and the like. In some embodiments of the invention, the compositions are administered locally, e.g. by injection or implantation at the site of an injury.