Compositions for inhibiting fibrin-VLDL receptor-dependent inflammation and methods of treatment
Inventors
Medved, Leonid V. • Strickland, Dudley • Yakovlev, Sergiy
Assignees
University of Maryland Baltimore
Publication Number
US-12171802-B2
Publication Date
2024-12-24
Expiration Date
2037-06-02
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Abstract
The invention provides a method of treating inflammation, comprising administering to a subject in need thereof a therapeutically effective amount of an agent that inhibits binding of fibrin to Very Low Density Lipoprotein Receptor (VLDLR) or combination of this agent with agents inhibiting binding of fibrin to VE-cahherin (vascular endothelial cadherin).
Core Innovation
The invention provides a method of treating inflammation by administering a therapeutically effective amount of an agent that inhibits the binding of fibrin to the Very Low Density Lipoprotein Receptor (VLDLR). Specifically, the method utilizes antibodies—most notably monoclonal antibodies 1H10 and 1H5—that target epitopes within the fibrin-binding domains of VLDLR. These antibodies have been shown to efficiently inhibit the interaction between fibrin and VLDLR, which is critical to the process of leukocyte transmigration during inflammation.
The problem addressed by this invention stems from findings that fibrinogen and its degradation products enhance inflammation through their interaction with endothelial cell receptors, including VLDLR. This interaction has been identified as a key driver of leukocyte transendothelial migration, a central step in the inflammatory response associated with tissue injury and diseases such as myocardial ischemia-reperfusion injury. Existing knowledge pointed to the need for specific inhibitors that can block this pathway and thereby ameliorate inflammation.
The core discovery is that the monoclonal antibodies 1H10 and 1H5 bind with high affinity to the fibrin-binding fragments of VLDLR and efficiently impede the interaction of fibrin with this receptor. This inhibition has been demonstrated both in vitro, where the antibodies block leukocyte transmigration induced by a fibrin-mimetic fragment, and in vivo, where administration of these antibodies in mouse models resulted in significant reduction of leukocyte infiltration and myocardial injury following ischemia and reperfusion. Additionally, the invention contemplates combinations of these VLDLR-targeting agents with agents that inhibit the binding of fibrin to VE-cadherin for broader anti-inflammatory effects.
Claims Coverage
The claims disclose three primary inventive features: (1) the use of antibodies with specific CDRs to inhibit fibrin-VLDLR binding after reperfusion, (2) the combination with fibrin beta chain peptides to further inhibit fibrin interactions, and (3) applicability to various forms of ischemia-reperfusion injury, including myocardial contexts.
Antibody inhibiting binding of fibrin to VLDLR after reperfusion
A method of treating a pathophysiological effect of ischemia and reperfusion by administering to a subject an antibody that comprises complementarity determining regions (CDRs) of antibody 1H10 after reperfusion, where the antibody inhibits the binding of fibrin to the Very Low Density Lipoprotein Receptor (VLDLR). - The antibody can bind at least one complement-type repeat (CR) domain of VLDLR selected from CR-2, CR-3, and CR-4. - The antibody administration can inhibit transendothelial migration of leukocytes, injury induced by ischemia and reperfusion, or specifically myocardial injury induced by ischemia and reperfusion. - The antibody may be monoclonal, humanized, or the 1H10 antibody itself.
Combination therapy with a fibrin beta chain peptide fragment
A method further comprising administering a therapeutically effective amount of a peptide comprising a fibrin beta chain fragment of the Bβ chain of fibrinogen in addition to the anti-VLDLR antibody. - The peptide may comprise an amino acid sequence with a non-naturally occurring residue and be other than the wild-type β15-42 monomer sequence and (β15-66)2 dimer sequence. - The peptide can be in monomeric or dimeric form, with dimers comprising specific linked peptides, and may inhibit binding of fibrin to VE-cadherin. - The peptide can be conjugated to, fused with, or combined with a protein transduction domain.
Application to various ischemia-reperfusion injuries and conditions
The method is applicable to treatment of myocardial ischemia and reperfusion as well as a wide range of ischemia-reperfusion events including hepatic, renal, intestinal, gastrointestinal, neuronal ischemia and reperfusion, ischemic neuropathies, surgery-induced ischemia and reperfusion, ischemia/reperfusion from organ transplantation, and preservation of transplanted organs. - The method is suitable for use in subjects suffering from or at risk of myocardial infarction or stroke, those suspected, susceptible to, or known to be undergoing ischemia and reperfusion, and in programmed or planned medical procedures (such as cardiac bypass surgery or angioplasty). - The method is described for use in acute rather than chronic conditions.
Collectively, these inventive features establish a therapeutic strategy using specific anti-VLDLR antibodies, optionally combined with fibrin beta chain peptides, to treat various acute ischemia-reperfusion-related pathologies by inhibiting fibrin-receptor interactions and subsequent inflammatory responses.
Stated Advantages
The administration of anti-VLDLR monoclonal antibodies (such as 1H10 and 1H5) efficiently inhibits leukocyte transendothelial migration and thereby reduces inflammation.
Treatment with these antibodies results in significant reduction of myocardial injury induced by ischemia-reperfusion in vivo, indicating strong cardioprotective effects.
The use of agents that inhibit fibrin-VLDLR interactions offers a novel, specific approach to block fibrin-dependent inflammation including applications in myocardial ischemia-reperfusion injury.
The combined administration of anti-VLDLR antibodies and agents that inhibit binding of fibrin to VE-cadherin provides broader inhibition of fibrin-mediated inflammatory pathways.
Documented Applications
Treatment of inflammation by inhibiting fibrin-VLDLR binding in conditions where leukocyte transmigration is implicated.
Treatment of myocardial injury induced by ischemia and reperfusion, including reducing infarct size after myocardial infarction.
Treatment of pathophysiological effects of ischemia and reperfusion in a subject, including but not limited to myocardial, hepatic, renal, intestinal, gastrointestinal, and neuronal ischemia and reperfusion, as well as ischemic neuropathies, surgical-induced ischemia and reperfusion, and organ transplantation.
Treatment of subjects suffering from, at risk of, or undergoing myocardial infarction, stroke, or various programmed/planned ischemia-reperfusion events (such as cardiac bypass surgery and angioplasty).
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