REGULATING THE INTERACTION BETWEEN TAM LIGANDS AND LIPID MEMBRANES WITH EXPOSED PHOSPHATIDYL SERINE
The present disclosure provides methods for modulating the interaction between a TAM ligand and a lipid membrane containing phosphatidyl serine (PtdSer). In one example, such methods use a TAM receptor agonist having a PtdSer-containing lipid bilayer membrane with Gas6 and/or Protein S bound to the membrane to activate signaling from one or more TAM receptors and treat an autoimmune disease. In another example, methods are provided for treating a subject with a pathological condition characterized by overactivation of TAM signaling and/or reduction in Type I IFN response, such as infection by an enveloped virus, by use of agents that decrease the interaction between a TAM ligand and PtdSer. Also provided are methods for classifying a virus as susceptible to anti-TAM therapy. Methods of identifying an agent that blocks virus infectivity are also provided.
1 .- 22 (canceled)
23 . A method of treating a pathological condition characterized by overactivation of TAM signaling or reduction in Type I IFN response in a subject, comprising administering to the subject in need thereof an antibody or antigen-binding fragment thereof specific for Gas6, wherein the antibody or antigen-binding fragment thereof disrupts the interaction between the Gla-domain of Gas6 and phosphatidyl serine containing membranes.
24 . The method of claim 23 , wherein the antibody or antigen-binding fragment thereof binds to the Gla-domain of Gas6 with a binding affinity of at least about 0.1×10 −8 M, at least about 0.3×10 −8 M, at least about 0.5×10 −8 M, at least about 0.75×10 −8 M, at least about 1.0×10 −8 M, at least about 1.3×10 −8 M at least about 1.5×10 −8 M, or at least about 2.0×10 −8 M.
25 . The method of claim 23 , wherein the antibody or antigen-binding fragment thereof is a chimeric antibody, humanized antibody, bispecific antibody, diabody, triabody, tetrabody, or a monoclonal antibody.
26 . The method of claim 23 , wherein the antigen-binding fragment is single chain Fv, F(ab′) 2 fragment, Fab′ fragment, Fab′-SH fragment, Fab fragment, Fv, sFv fragment, dsFv fragment, bispecific sFv fragment, bispecific dsFv fragment, complementarity determining region (CDR) fragment, or camelid antibody.
27 . The method of claim 23 , wherein the pathological condition is characterized by overactivation of Axl signaling, Mer signaling, and/or Tyro3 signaling.
28 . The method of claim 23 , wherein the pathological condition is characterized by overactivation of Axl signaling.
29 . The method of claim 23 , wherein the pathological condition is characterized by overactivation of Mer signaling.
30 . The method of claim 23 , wherein the pathological condition is characterized by overactivation of Tyro3 signaling.
31 . The method of claim 23 , wherein the pathological condition is cancer.
32 . The method of claim 23 , wherein the pathological condition is a virus infection.
33 . The method of claim 32 , wherein the virus is an enveloped virus.
34 . The method of claim 23 , wherein the antibody or antigen-binding fragment is an active ingredient in a pharmaceutical composition.
35 . The method of claim 23 , further comprising administering to the subject an additional therapeutic agent.
36 . The method of claim 35 , wherein the additional therapeutic agent is an anti-viral agent.
37 . The method of claim 35 , wherein the additional therapeutic agent stimulates the immune system.
38 . The method of claim 35 , wherein the additional therapeutic agent is an IFN, cytokine, interleukin, or other agent that increases cytokine production.