Mitigating tissue damage and fibrosis via latent transforming growth factor beta binding protein (LTBP4)
The disclosure relates to compositions and methods of mitigating tissue damage and fibrosis in a patient by modulating latent transforming growth factor beta binding protein (LTBP4)-induced proteolysis of a Transforming Growth Factor-beta (TGFβ) superfamily protein.
1. An isolated antibody that specifically binds to the sequence set forth in SEQ ID NO: 6.
2. A pharmaceutical formulation comprising the antibody of claim 1 and a pharmaceutically acceptable carrier or diluent.
3. The formulation of claim 2 , further comprising a second agent, wherein the second agent is selected from the group consisting of a modulator of an inflammatory response, a promoter of muscle growth, a chemotherapeutic agent and a modulator of fibrosis.
4. A kit comprising the antibody of claim 1 , a pharmaceutically acceptable carrier or diluent, and instructions for use.
5. The kit of claim 4 , further comprising a second agent, wherein the second agent is selected from the group consisting of a modulator of an inflammatory response, a promoter of muscle growth, a chemotherapeutic agent and a modulator of fibrosis.
6. A method of treating a patient having Duchenne Muscular Dystrophy, Limb Girdle Muscular Dystrophy, Becker Muscular Dystrophy, myopathy, pulmonary fibrosis, cardiomyopathy, acute lung injury, acute skeletal muscle injury, or acute myocardial injury, comprising administering the antibody of claim 1 to the patient.
7. The method of claim 6 further comprising administering a second agent, wherein the second agent is selected from the group consisting of a modulator of an inflammatory response, a promoter of muscle growth, a chemotherapeutic agent, and a modulator of fibrosis.
8. The method of claim 7 wherein the promoter of muscle growth is selected from the group consisting of insulin-like growth factor-1 (IGF-1), Akt/protein kinase B, clenbuterol, creatine, decorin, a steroid, and testosterone.
9. The method of claim 7 wherein the second agent is selected from the group consisting of an antibody to growth and differentiation factor-8 (GDF-8), an antibody to a GDF-8 receptor, a soluble GDF-8 receptor, a GDF-8 propeptide, follistatin, and a follistatin-domain-containing protein.
10. The method of claim 7 wherein the modulator of an inflammatory response is cyclosporin.
11. The method of claim 7 wherein the chemotherapeutic agent is selected from the group consisting of an alkylating agent, a nitrosourea, a ethylenimines/methylmelamine, an alkyl sulfonate, a triazine, an antimetabolite, a pyrimidine analog, a purine analog, an antimitotic drug, an epipodophylotoxin, an antibiotic, L-asparaginase, interferon-alpha, interleukin-2 (IL-2), granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), cisplatin, carboplatin, en anthracenedione, substituted urea, a methylhydrazine derivative, an adrenocortical suppressant, an adrenocorticosteroid antagonist, progestin, estrogen, antiestrogen, an androgen, an antiandrogen, a gonadotropin-releasing hormone analog, and a non-steroidal antiandrogen.
12. The method of claim 7 wherein the modulator of fibrosis is selected from the group consisting of pirfenidone, an angiotensin-converting-enzyme (ACE) inhibitor, an angiotensin receptor blocker, and an aldosterone antagonist.