METHODS AND COMPOSITIONS FOR IMMUNOTHERAPY AND DETECTION OF INFLAMMATORY AND IMMUNE-DYSREGULATORY DISEASE, INFECTIOUS DISEASE, PATHOLOGIC ANGIOGENESIS AND CANCER
Methods and compositions for immunotherapy of inflammatory and immune-dysregulatory diseases, using multispecific antagonists that target at least two different markers are disclosed. The different targets include (i) proinflammatory effectors of the innate immune system, (ii) coagulation factors, and (iii) targets specifically associated with an inflammatory or immune-dysregulatory disorder, with a pathologic angiogenesis or cancer, or with an infectious disease, wherein the targets included in group (iii) are neither a proinflammatory effector of the immune system nor a coagulation factor. When the multispecific antagonist reacts specifically with a target associated with an inflammatory or immune-dysregulatory disorder, with a pathologic angiogenesis or cancer, or with an infectious disease, it also binds specifically with at least one proinflammatory effector of the immune system or at least one coagulation factor. Thus, the multispecific antagonist contains at least one binding specificity related to the diseased cell or condition being treated and at least one specificity to a component of the immune system, such as a receptor or antigen of B cells, T cells, neutrophils, monocytes and macrophages, and dendritic cells, a modulator of coagulation, or a proinflammatory cytokine. The multispecific antagonists are used in the treatment of various diseases that are generated or exacerbated by, or otherwise involve, proinflammatory effectors of the innate immune system or coagulation factors. Such diseases more particularly include acute and chronic inflammatory disorders, autoimmune diseases, giant cell arteritis, septicemia and septic shock, coagulopathies (including diffuse intravascular coagulation), neuropathies, graft versus host disease, infectious diseases, acute respiratory distress syndrome, granulomatous diseases, transplant rejection, asthma, cachexia, myocardial ischemia, and atherosclerosis. Other diseases also responsive to these therapies include cancers and conditions with pathological angiogenesis.
1 . A multispecific antagonist that reacts specifically with at least two: different targets, wherein said targets are selected from the group consisting of (A) proinflammatory effectors of the innate immune system, (B) coagulation factors, (C) complement factors and complement regulatory proteins, and (D) targets specifically associated with an inflammatory or immune-dysregulatory disorder or with a pathologic angiogenesis or cancer, wherein said latter target is not (A), (B) or (C), and wherein
(i) at least one of said targets is (B),
(ii) when said multispecific antagonist comprises a single multispecific antibody, then CD74 is excluded as a target of said antagonist, and
(iii) when said multispecific antagonist comprises a combination of separate antibodies, combinations are excluded where one of said antibodies targets a B-cell antigen and the other antibody targets a T-cell, plasma cell, macrophage or inflammatory cytokine and combinations are also excluded where one of said antibodies targets CD20 and the other antibody targets C3b or CD40.
2 . A multispecific antagonist according to claim 1 , which is a combination of two separate antibodies.
3 . A multispecific antagonist according to claim 1 , which is a multispecific antibody.
4 . A multispecific antagonist according to claim 1 , which is a fusion protein.
5 . A multispecific antagonist according to claim 1 , wherein one of said two different targets is a target (D).
6 . A multispecific antagonist according to claim 1 , wherein one of said two different targets is a target (A) or (C).
7 . A multispecific antagonist according to claim 1 , wherein when said multispecific antagonist comprises a combination of separate antibodies, combinations are excluded where one of said antibodies targets CD19, CD20, CD21, CD22, CD23 or CD80 and the other antibody targets a complement factor.
8 . A multispecific antagonist according to claim 1 , wherein said antagonist reacts specifically with two different coagulation factors.
9 . A multispecific antagonist according to claim 1 , wherein said antagonist reacts specifically with at least one proinflammatory effector of the innate immune system and with at least one coagulation factor.
10 . A multispecific antagonist according to claim 1 , wherein said antagonist reacts specifically with at least one coagulation factor and with at least one complement factor or complement regulatory protein.
11 . A multispecific antagonist according to claim 1 , wherein said antagonist comprises at least one soluble receptor.
12 . A multispecific antagonist according to claim 1 , wherein said antagonist comprises at least one soluble receptor fused to at least one antibody.
13 . A multispecific antagonist according to claim 1 that targets dendritic cells, granulocytes, monocytes, macrophages, NK-cells, platelets, or endothelial cells.
14 . A multispecific antagonist according to claim 1 that targets an antigen or receptor of the adaptive immune system.
15 . A multispecific antagonist according to claim 1 that targets a cancer cell receptor or cancer-associated antigen.
16 . A multispecific antagonist according to claim 1 , wherein said antagonist comprises an antibody that is at least bispecific, in which at least one arm reacts specifically with said coagulation factor and at least one arm reacts with said proinflammatory effector.
17 . A multispecific antagonist according to claim 1 , wherein said antagonist comprises an antibody that is at least bispecific, in which at least one arm reacts specifically with said complement factor or complement regulatory protein and at least one arm reacts with said coagulation factor.
18 . A multispecific antagonist according to claim 1 , wherein said antagonist comprises an antibody that is at least bispecific, in which at least one arm reacts specifically with target (B) and at least one arm reacts with target (D).
19 . A multispecific antagonist according to claim 1 , wherein said antagonist comprises a single active component.
20 . A multispecific antagonist according to claim 1 , additionally comprising a secondary therapeutic that affects a component of the innate immune system.
21 . A multispecific antagonist according to claim 1 , additionally comprising a secondary therapeutic that affects coagulation.
22 . A multispecific antagonist according to claim 1 , additionally comprising a secondary therapeutic that affects a component of the adaptive immune system.
23 . A multispecific antagonist according to claim 1 , wherein said at least one other target is associated with an infectious disease, acute respiratory distress syndrome, septicemia or septic shock, graft versus host disease or transplant rejection, atherosclerosis, asthma, granulomatous disease, a neuropathy, cachexia, a coagulopathy, acne, giant cell arteritis, or myocardial ischemia.
24 . A multispecific antagonist according to claim 1 , wherein said antagonist comprises a diagnostic/detection agent.
25 . A multispecific antagonist according to claim 1 , wherein said antagonist is an immunoconjugate that comprises a therapeutic agent.