METHODS AND COMPOSITIONS TO REDUCE LIVER DAMAGE ASSOCIATED WITH CONDITIONS OR THERAPIES THAT AFFECT THE IMMUNE SYSTEM
One side-effect arising from the use of antibodies against TNF receptor family members as therapeutics can be liver damage which precludes the completion of clinical trial. A novel LT-dependent pathway is described that mediates liver cell injury in several disease models.
1 . A method to reduce liver damage in a mammal, the method comprising administering to the mammal an agent that interferes with the LT or TNF pathways.
2 . The method of claim 1 wherein the liver damage is associated with treatment of the mammal by an antibody selected from the group consisting of anti-CD137, anti-CTLA-4, anti-GITR, anti-B7-H1, anti-PD-1, anti-B7-H3 and anti-B7x.
3 . A composition comprising an agent that interferes with a component of the LT pathway and a therapeutic agent directed at a disease or condition.
4 . The composition of claim 3 , wherein the component of the LT pathway is lymphotoxin (LT).
5 . The composition of claim 4 wherein the agent that interferes with a component of the LT pathway interferes with LTβR signaling.
6 . The composition of claim 3 wherein the agent that interferes with a component of the LT pathway comprises a soluble form of the LTβR or its equivalent.
7 . The composition of claim 3 wherein the agent that interferes with a component of the LT pathway comprises the extracellular domain of LTβR fused to a human IgG Fc domain.
8 . The composition of claim 3 wherein the agent that interferes with a component of the LT pathway is an antagonistic antibody against LTβR or LT.
9 . The composition of claim 3 wherein the disease is selected from the group consisting of an autoimmune disease, viral hepatitis and cancer.
10 . A composition comprising an agent that interferes with a component of the TNF pathway and a therapeutic agent directed at a disease or condition.
11 . The composition of claim 10 wherein the component of the TNF pathway is TNF.
12 . The composition of claim 10 wherein the agent that interferes with a component of the TNF pathway comprises a soluble form of a TNFR or its equivalent.
13 . The composition of claim 10 wherein the agent that interferes with a component of the TNF pathway is selected from the group consisting of Infliximab, mouse-human chimeric anti-huTNF mAb, D2E7, fully human anti-huTNF mAb, p75sTNF-RII-Fc, PEG-p55sTNF-RI, p55sTNF-RI-IgG1, CDP571, PEG-linked anti TNF Fab, competitive TNF antagonists, and TNF siRNAs.
14 . The composition of claim 10 wherein the disease is selected from the group consisting of an autoimmune disease, viral hepatitis and cancer.
15 . The composition of claim 10 wherein the therapeutic agent is an antibody that targets coinhibitory or costimulatory T cell receptors.
16 . A pharmaceutical composition to alleviate hepatic injury induced by therapies, the composition comprising an agonistic CD137 antibody and an anti-TNF or anti-LT therapy.
17 . The pharmaceutical composition of claim 21 wherein the agonistic CD137 antibody is BMS-663513.
18 . The method of claim 1 where the mammal is a human.
19 . The method of claim 1 wherein the agent is selected from the group consisting of an antibody and a soluble receptor.