Biomarkers of immunomodulatory effects in humans treated with anti-cd200 antibodies

Abstract

The present disclosure relates to anti-CD200 antibodies (e.g., variant anti-CD200 antibodies having decreased or no effector function) and to biomarkers for use in a variety of diagnostic and therapeutic methods, e.g., determining whether a human has been administered one or more of the antibodies at a dose sufficient to induce a desired immunomodulatory effect in the human and/or selecting an appropriate dosing schedule for a patient.

1 - 266 . (canceled) 
     
     
         267 . A method for determining whether an anti-CD200 antibody or an antigen-binding fragment thereof has produced a desired anti-CD200 antibody-associated immunomodulatory effect in a human, the method comprising detecting a change in at least one anti-CD200 antibody-associated immunomodulatory biomarker in a biological sample obtained from a human after administration of an anti-CD200 antibody or antigen-binding fragment thereof to the human, wherein the change in at least one anti-CD200 antibody-associated immunomodulatory biomarker is selected from the group consisting of:
 (i) a reduction in the concentration of regulatory T cells in the biological sample, relative to the concentration of regulatory T cells of the same histological type in a biological sample obtained from the human prior to administration of the antibody or antigen-binding fragment thereof;   (ii) an increase in the concentration of CD8 +  T cells in the biological sample, relative to the concentration of CD8 +  T cells of the same histological type in a biological sample obtained from the human prior to administration of the antibody or antigen-binding fragment thereof;   (iii) an increase in the concentration of CD4 +  T cells in the biological sample, relative to the concentration of CD4 +  T cells of the same histological type in a biological sample obtained from the human prior to administration of the antibody or antigen-binding fragment thereof;   (iv) an increase in the concentration of activated T cells in the biological sample, relative to the concentration of activated T cells of the same histological type in a biological sample obtained from the human prior to administration of the antibody or antigen-binding fragment thereof;   (v) a reduction in the concentration of CD200 +  leukocytes in the biological sample, relative to the concentration of CD200 +  leukocytes of the same histological type in a biological sample obtained from the human prior to administration of the antibody or antigen-binding fragment thereof;   (vi) an increase in the concentration of CD200R +  leukocytes in the biological sample, relative to the concentration of CD200R +  leukocytes of the same histological type in a biological sample obtained from the human prior to administration of the antibody or antigen-binding fragment thereof;   (vii) a ratio of percent activated T cells to percent regulatory T cells of at least 2:1 in the biological sample obtained from the patient after administration to the patient of the anti-CD200 antibody or antigen-binding fragment thereof;   (viii) a ratio of percent activated T cells to percent regulatory T cells of at least 3:1 in the biological sample obtained from the patient after administration to the patient of the anti-CD200 antibody or antigen-binding fragment thereof;   (ix) a ratio of percent activated T cells to percent regulatory T cells of at least 4:1 in the biological sample obtained from the patient after administration to the patient of the anti-CD200 antibody or antigen-binding fragment thereof;   (x) a ratio of percent activated T cells to percent regulatory T cells of at least 5:1 in the biological sample obtained from the patient after administration to the patient of the anti-CD200 antibody or antigen-binding fragment thereof;   (xi) a ratio of percent activated T cells to percent regulatory T cells of at least 6:1 in the biological sample obtained from the patient after administration to the patient of the anti-CD200 antibody or antigen-binding fragment thereof;   (xii) an increase in the ratio of percent activated T cells to percent regulatory T cells in the biological sample, relative to the corresponding ratio of percent activated T cells to percent regulatory T cells of the same histological type in a biological sample obtained from the human prior to administration of the antibody or antigen-binding fragment thereof;   (xiii) a decreased level of CD200 expression by a plurality of leukocytes in the biological sample, relative to the level of CD200 expression by a plurality of leukocytes of the same histological type in a biological sample from the human prior to administration of the antibody or antigen-binding fragment thereof;   (xiv) an increased level of CD200R expression by a plurality of leukocytes in the biological sample, relative to the level of CD200R expression by a plurality of leukocytes in a biological sample obtained from the human prior to administration of the anti-CD200 antibody or antigen-binding fragment thereof;   (xv) a decrease in the concentration of one or more CD200 +  bone marrow subsets in the biological sample, relative to the concentration of the corresponding one or more CD200 +  bone marrow subsets in a biological sample obtained from the human prior to administration of the anti-CD200 antibody or antigen-binding fragment thereof;   (xvi) a decrease in the level of CD200 expression by a plurality of lymphocytes in the biological sample, relative to the level of CD200 expression by a plurality of lymphocytes of the same histological type in a biological sample obtained from the human prior to administration of the anti-CD200 antibody or antigen-binding fragment thereof, wherein the lymphocytes are bone marrow cells or splenic cells; and   (xvii) a decrease in tumor burden as measured by imaging.   
     
     
         268 . The method of  claim 267 , wherein the detecting occurs within or less than eight weeks, seven weeks, six weeks, five weeks, four weeks, three weeks, or two weeks after administration of the antibody or antigen-binding fragment thereof. 
     
     
         269 . The method of  claim 267 , wherein the human is afflicted with a cancer. 
     
     
         270 . The method of  claim 267 , wherein the human has, is suspected of having, or is at risk for developing, an inflammatory disorder or a bone disorder. 
     
     
         271 . The method of  claim 269 , wherein the cancer is chronic lymphocytic leukemia (CLL). 
     
     
         272 . The method of  claim 269 , wherein the cancer is a solid tumor. 
     
     
         273 . The method of  claim 272 , wherein the solid tumor is a colon cancer, a breast cancer, a lung cancer, a renal cancer, a pancreatic cancer, a thyroid cancer, a skin cancer, a cancer of the nervous system, a cervical cancer, an ovarian cancer, a testicular cancer, a head and neck cancer, a cancer of the eye, a stomach cancer, or a liver cancer. 
     
     
         274 . The method according to  claim 273 , wherein the cancer of the nervous system is a neuroblastoma. 
     
     
         275 . The method according to  claim 267 , wherein the per-dose amount of the anti-CD200 antibody or antigen-binding fragment thereof administered to the patient is at least: (i) 100 mg/m 2  of the patient; (ii) 200 mg/m 2  of the patient; (iii) 300 mg/m 2  of the patient; (iv) 400 mg/m 2  of the patient, or (v) 500 mg/m 2  of the patient. 
     
     
         276 . The method of  claim 267 , wherein the anti-CD200 antibody or an antigen-binding fragment thereof is administered to the patient at least once per week, at least once every two weeks, at least once every three weeks, or at least once every four weeks. 
     
     
         277 . The method of  claim 272 , wherein the solid tumor is reduced in mass. 
     
     
         278 . The method of  claim 277 , wherein the solid tumor is reduced in mass by at least about 57.6%. 
     
     
         279 . The method of  claim 267 , wherein the anti-CD200 antibody is a murine antibody, a chimeric antibody, a humanized antibody, or a human antibody. 
     
     
         280 . The method of  claim 267 , wherein the antigen-binding fragment is selected from the group consisting of an Fab, an F(ab′) 2 , an Fv, and a single-chain antibody. 
     
     
         281 . The method of  claim 267 , wherein the anti-CD200 antibody or antigen-binding fragment thereof comprises a variant constant region that has decreased or no effector function, relative to a non-variant form of the constant region. 
     
     
         282 . The method of  claim 267 , wherein the anti-CD200 antibody or antigen-binding fragment thereof inhibits the interaction between CD200 and CD200R. 
     
     
         283 . A method for selecting a cancer patient for treatment with an anti-CD200 antibody or an antigen-binding fragment thereof, the method comprising:
 determining whether the immune system of a patient with cancer is competent to mount an immune response against the cancer; and   if the patient's immune system is determined to be competent, selecting the patient for an anti-CD200 antibody or antigen-binding fragment thereof therapy.   
     
     
         284 . The method of  claim 283 , wherein the patient's immune system is determined to be competent to mount an immune response against the cancer in the presence of the anti-CD200 antibody or an antigen-binding fragment thereof. 
     
     
         285 . The method of  claim 283 , wherein the patient's immune system is determined to be competent to mount an immune response against the cancer in the absence of the anti-CD200 antibody or antigen-binding fragment thereof. 
     
     
         286 . The method of  claim 283 , wherein the determining comprises measuring:
 (i) the absolute number of CD8 +  T cells per microliter of blood obtained from the patient prior to administering the anti-CD200 antibody or antigen-binding fragment thereof; or   (ii) the absolute number per microliter of blood of at least one immune cell population in the patient prior to administering the anti-CD200 antibody or antigen-binding fragment thereof, wherein the at least one immune cell population is selected from the group consisting of CD4 +  helper T cells, non-cancer CD45 +  lymphocytes, CD19 +  B cells, CD16 + CD56 + natural Killer (NK) cells, and CD3 +  cells.