Doses of antibodies which bind human fibrin yc or fibrinogen yc domain for ocular diseases

Abstract

Described herein are dosage forms of antibodies that bind fibrin γC or fibrinogen γC, methods of use, and dosage regimens thereof. In certain aspects, the antibodies and methods described herein are used for treatment of disorder or condition of the eye.

Description

DOSES OF ANTIBODIES WHICH BIND HUMAN FIBRIN yC OR FIBRINOGEN yC DOMAIN FOR OCULAR DISEASESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 642,155, filed on May 3, 2024, the disclosure of which is hereby incorporated by reference in its entirety for all purposes.SEQUENCE LISTING

[0002] This application contains a Sequence Listing XML, which has been submitted electronically and is hereby incorporated by reference in its entirety. The XML copy of the Sequence Listing, created on May 1, 2025, is named THB-013WO_SL.xml and is 256,332 bytes in size.BACKGROUND

[0003] Microglia are resident immune cells of the central nervous system (CNS), including the retina. Microglia have been implicated in many degenerative eye disorders, including retinitis pigmentosa, age-related macular degeneration (AMD), glaucoma, diabetic retinopathy (e.g., diabetic macular edema), uveitis, and retinal detachment. While these diseases differ in their underlying etiologies, they are all characterized by the loss of photoreceptors or retinal ganglion cells (RGCs), resulting in deterioration of vision and, in some cases, blindness. Activation of microglia contributes to both neuronal and oligodendrocyte death via release of cytokines and nitric oxide. It is possible that interventions targeting activated microglia could alleviate photoreceptor and RGC death, thereby helping patients preserve their sight.

[0004] The y377-395 epitope of the fibrin yC or fibrinogen yC domain is the binding epitope of fibrin to CD1 lb / CD18 (Mac-1) (also referred to as: Mac-1, aMfl 2, and Complement Receptor 3) and CD1 lc / CD18 (also referred to as: Complement Receptor 4) which are present on innate immune cells including microglia, macrophages, neutrophils and dendritic cells Delivery of the fibrin-derived y377 -395 inhibitory peptide impedes this interaction and bocks microglia activation by blocking fibrin binding to CD1 lb / CD18 (Mac- 1) and CD1 lc / CD18. Because fibrin mediates blood coagulation by binding via a distinct epitope to the platelet integrin aubPs receptor, therapeutic agents (including antibodies), that block the CD1 lb / CD18 (Mac-1) and CD1 lc / CD18 binding epitope to fibrin can reduce thedamaging effects of fibrin in the nervous system without affecting its beneficial effects in blood coagulation.

[0005] Fibrin deposition and impaired fibrinolysis have long been implicated as a driver of chronic inflammation secondary to loss of vascular integrity in many central nervous system (CNS) and peripheral inflammatory diseases. Dysregulation of the blood-retinal- barrier (BRB) is associated with disorders and conditions of the eye and allows fibrinogen to enter the CNS. Fibrinogen is elevated in the vitreous humor of patients with diabetic retinopathy (DR) and age-related macular degeneration (AMD) and extravasated fibrinogen forms in exudates and areas of hemorrhage. Loss of vascular integrity and microglia and astrocyte transcriptional signatures are present in AMD.

[0006] Angiogenic ocular conditions such as retinopathy of prematurity, diabetic retinopathy, diabetic macular edema, and age-related macular degeneration represent the leading cause of irreversible vision loss in developed countries. Breakdown of the bloodretina barrier Evidence suggests that vascular endothelial growth factor (VEGF) promotes angiogenesis in each of these conditions.

[0007] Therefore, safe, effective therapeutics that inhibit fibrin-induced microglial and macrophage activation without affecting its beneficial effects in blood coagulation, and that also block VEGF, are needed for treatment of disorders and conditions of the eye.SUMMARY

[0008] Described herein, in some embodiments, are dosage forms comprising an isolated antibody that binds human fibrin yC or fibrinogen yC domain, wherein the dosage form comprises the isolated antibody at a concentration of from about 20 mg / mL to about 200 mg / mL, and wherein the isolated antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR- H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein, respectively: CDR-H1 comprises the sequence set forth in SEQ ID NOs: 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181, 193, 205, 217, or 229; CDR-H2 comprises the sequence set forth in SEQ ID NOs: 2, 14, 26, 38, 50, 62, 74, 86, 98, 110, 122, 134, 146, 158, 170, 182, 194, 206, 218, or 230; CDR-H3 comprises the sequence set forth in SEQ ID NOs: 3, 15, 27, 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 159, 171, 183, 195, 207, 219, or 231; CDR-L1 comprises the sequence set forth in SEQ ID NOs: 4, 16, 28, 40, 52, 64, 76, 88, 100, 112, 124, 136, 148, 160, 172, 184, 196, 208, 220, or 232; CDR-L2 comprises the sequenceset forth in SEQ ID NOs: 5, 17, 29, 41, 53, 65, 77, 89, 101, 113, 125, 137, 149, 161, 173, 185, 197, 209, 221, or 233; and CDR-L3 comprises the sequence set forth in SEQ ID NOs: 6, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, or 234.

[0009] In some embodiments, the dosage form is formulated for local (e.g., intravitreal, subconjunctival, retrobulbar, and intracameral), topical, or systemic administration.

[0010] In some embodiments, the dosage form is formulated for intravitreal administration.

[0011] In some embodiments, the dosage form comprises the isolated antibody at a concentration of greater than about 40, 60, 80, 100, 120, 160, 180, or 200 mg / mL.

[0012] In some embodiments, the dosage form comprises the isolated antibody at a concentration of about 100 mg / mL.

[0013] Also described herein, in some embodiments, are methods of treating a disorder or condition of the eye in a subject in need thereof, the method comprising administering to the subject a dosage form comprising an isolated antibody that binds human fibrin yC or fibrinogen yC domain, wherein the dosage form comprises the isolated antibody at a concentration of from about 20 mg / mL to about 200 mg / mL, and wherein the isolated antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein, respectively: CDR-H1 comprises the sequence set forth in SEQ ID NOs: 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181, 193, 205, 217, or 229; CDR-H2 comprises the sequence set forth in SEQ ID NOs: 2, 14, 26, 38, 50, 62, 74, 86, 98, 110, 122, 134, 146, 158, 170, 182, 194, 206, 218, or 230; CDR-H3 comprises the sequence set forth in SEQ ID NOs: 3, 15, 27, 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 159, 171, 183, 195, 207, 219, or 231; CDR-Ll comprises the sequence set forth in SEQ ID NOs: 4, 16, 28, 40, 52, 64, 76, 88, 100, 112, 124, 136, 148, 160, 172, 184, 196, 208, 220, or 232; CDR-L2 comprises the sequence set forth in SEQ ID NOs: 5, 17, 29, 41, 53, 65, 77, 89, 101, 113, 125, 137, 149, 161, 173, 185, 197, 209, 221, or 233; and CDR-L3 comprises the sequence set forth in SEQ ID NOs: 6, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, or 234.

[0014] Also described herein, in some embodiments, are methods of treating a disorder or condition of the eye in a subject in need thereof, the method comprising administering to the subject a dosage form comprising a means for binding human fibrin yC or fibrinogen yCdomain, wherein the dosage form comprises the means for binding human fibrin yC or fibrinogen yC domain at a concentration of from about 20 mg / mL to about 200 mg / mL.

[0015] In some embodiments, the dosage form comprises the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain at a concentration of greater than about 40, 60, 80, 100, 120, 160, 180, or 200 mg / mL.

[0016] In some embodiments, the dosage form comprises the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain at a concentration of about 100 mg / mL.

[0017] Also described herein, in some embodiments, are methods of treating a disorder or condition of the eye in a subject in need thereof, the method comprising administering to the subject one or more doses of a dosage form comprising an isolated antibody that binds human fibrin yC or fibrinogen yC domain, each dose selected from about 1 mg to about 20 mg to each eye of the isolated antibody, wherein the isolated antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein, respectively: CDR-H1 comprises the sequence set forth in SEQ ID NOs: 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181, 193, 205, 217, or 229; CDR-H2 comprises the sequence set forth in SEQ ID NOs: 2, 14, 26, 38, 50, 62, 74, 86, 98, 110, 122, 134, 146, 158, 170, 182, 194, 206, 218, or 230; CDR-H3 comprises the sequence set forth in SEQ ID NOs: 3, 15, 27, 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 159, 171, 183, 195, 207, 219, or 231; CDR-L1 comprises the sequence set forth in SEQ ID NOs: 4, 16, 28, 40, 52, 64, 76, 88, 100, 112, 124, 136, 148, 160, 172, 184, 196, 208, 220, or 232; CDR-L2 comprises the sequence set forth in SEQ ID NOs: 5, 17, 29, 41, 53, 65, 77, 89, 101, 113, 125, 137, 149, 161, 173, 185, 197, 209, 221, or 233; and CDR-L3 comprises the sequence set forth in SEQ ID NOs: 6, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, or 234.

[0018] Also described herein, in some embodiments, are methods of treating a disorder or condition of the eye in a subject in need thereof, the method comprising administering to the subject one or more doses of a dosage form comprising a means for binding human fibrin yC or fibrinogen yC domain, each dose selected from about 1 mg to about 20 mg to each eye of the means for binding human fibrin yC or fibrinogen yC domain.

[0019] In some embodiments, the isolated antibody comprises a VH sequence selected from a sequence set forth in any one of SEQ ID NOs: 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 163, 175, 187, 199, 211, 223, or 235.

[0020] In some embodiments, the isolated antibody comprises a VL sequence selected from a sequence set forth in SEQ ID NOs: 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 166, 178, 190, 202, 214, 226, or 238.

[0021] In some embodiments, the isolated antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 10. In some embodiments, the isolated antibody comprises a VH sequence set forth in SEQ ID NO: 19 and a VL sequence set forth in SEQ ID NO: 22. In some embodiments, the isolated antibody comprises a VH sequence set forth in SEQ ID NO: 31 and a VL sequence set forth in SEQ ID NO: 34. In some embodiments, the isolated antibody comprises a VH sequence set forth in SEQ ID NO: 43 and a VL sequence set forth in SEQ ID NO: 46. In some embodiments, the isolated antibody comprises a VH sequence set forth in SEQ ID NO: 55 and a VL sequence set forth in SEQ ID NO: 58. In some embodiments, the isolated antibody comprises a VH sequence set forth in SEQ ID NO: 67 and a VL sequence set forth in SEQ ID NO: 70. In some embodiments, the isolated antibody comprises a VH sequence set forth in SEQ ID NO: 79 and a VL sequence set forth in SEQ ID NO: 82. In some embodiments, the isolated antibody comprises a VH sequence set forth in SEQ ID NO: 91 and a VL sequence set forth in SEQ ID NO: 94. In some embodiments, the isolated antibody comprises a VH sequence set forth in SEQ ID NO: 103 and a VL sequence set forth in SEQ ID NO: 106. In some embodiments, the isolated antibody comprises a VH sequence set forth in SEQ ID NO: 115 and a VL sequence set forth in SEQ ID NO: 118. In some embodiments, the isolated antibody comprises a VH sequence set forth in SEQ ID NO: 127 and a VL sequence set forth in SEQ ID NO: 130. In some embodiments, the isolated antibody comprises a VH sequence set forth in SEQ ID NO: 139 and a VL sequence set forth in SEQ ID NO: 142. In some embodiments, the isolated antibody comprises a VH sequence set forth in SEQ ID NO: 151 and a VL sequence set forth in SEQ ID NO: 154. In some embodiments, the isolated antibody comprises a VH sequence set forth in SEQ ID NO: 163 and a VL sequence set forth in SEQ ID NO: 166. In some embodiments, the isolated antibody comprises a VH sequence set forth in SEQ ID NO: 175 and a VL sequence set forth in SEQ ID NO: 178. In some embodiments, the isolated antibody comprises a VH sequence set forth in SEQ ID NO: 187 and a VL sequence set forth in SEQ ID NO: 190. In some embodiments, the isolated antibody comprises a VH sequence set forthin SEQ ID NO: 199 and a VL sequence set forth in SEQ ID NO: 202. In some embodiments, the isolated antibody comprises a VH sequence set forth in SEQ ID NO: 211 and a VL sequence set forth in SEQ ID NO: 214. In some embodiments, the isolated antibody comprises a VH sequence set forth in SEQ ID NO: 223 and a VL sequence set forth in SEQ ID NO: 226. In some embodiments, the isolated antibody comprises a VH sequence set forth in SEQ ID NO: 235 and a VL sequence set forth in SEQ ID NO: 238. In some embodiments, the isolated antibody comprises a VH sequence set forth in SEQ ID NO: 256 and a VL sequence set forth in SEQ ID NO: 257.

[0022] In some embodiments, in the isolated antibody comprises a humanized, human, or chimeric antigen binding region. In some embodiments, the isolated antibody comprises a humanized antibody or antigen binding region.

[0023] In some embodiments, the isolated antibody comprises a heavy chain human Fc region of a class selected from IgG, IgA, IgD, IgE, and IgM.

[0024] In some embodiments, the human Fc region comprises a human heavy chain constant region of the class IgG and a subclass selected from IgGl, IgG2, IgG3, and IgG4.

[0025] In some embodiments, the human Fc region comprises wild-type, human IgGl Fc.

[0026] In some embodiments, the human Fc domain comprises a sequence set forth in SEQ ID NOs: 8, 20, 32, 44, 56, 68, 80, 92, 104, 116, 128, 140, 152, 164, 176, 188, 200, 212, 224, or 236.

[0027] In some embodiments, the heavy chain comprises a constant heavy chain sequence set forth by SEQ ID NO s: 8, 20, 32, 44, 56, 68, 80, 92, 104, 116, 128, 140, 152, 164, 176, 188,200, 212, 224, or 236.

[0028] In some embodiments, the light chain comprises a constant light chain sequence set forth by SEQ ID NO s: 9, 21, 33, 45, 57, 69, 81, 93, 105, 117, 129, 141, 153, 165, 177, 189,201, 213, 225, or 237.

[0029] In some embodiments, the isolated antibody comprises the VH sequence set forth in SEQ ID NO: 7, and the VL sequence set forth in SEQ ID NO: 10; and the human Fc region comprises wild-type, human IgGl Fc. In some embodiments, the isolated antibody comprises the VH sequence set forth in SEQ ID NO: 19, and the VL sequence set forth in SEQ ID NO: 22; and the human Fc region comprises wild-type, human IgGl Fc. In some embodiments, the isolated antibody comprises the VH sequence set forth in SEQ ID NO: 31, and the VL sequence set forth in SEQ ID NO: 34; and the human Fc region comprises wild-type, human IgGl Fc. In some embodiments, the isolated antibody comprises the VH sequence set forth inSEQ ID NO: 43, and the VL sequence set forth in SEQ ID NO: 46; and the human Fc region comprises wild-type, human IgGl Fc. In some embodiments, the isolated antibody comprises the VH sequence set forth in SEQ ID NO: 55, and the VL sequence set forth in SEQ ID NO: 58; and the human Fc region comprises wild-type, human IgGl Fc. In some embodiments, the isolated antibody comprises the VH sequence set forth in SEQ ID NO: 67, and the VL sequence set forth in SEQ ID NO: 70; and the human Fc region comprises wild-type, human IgGl Fc. In some embodiments, the isolated antibody comprises the VH sequence set forth in SEQ ID NO: 79, and the VL sequence set forth in SEQ ID NO: 82; and the human Fc region comprises wild-type, human IgGl Fc. In some embodiments, the isolated antibody comprises the VH sequence set forth in SEQ ID NO: 91, and the VL sequence set forth in SEQ ID NO: 94; and the human Fc region comprises wild-type, human IgGl Fc. In some embodiments, the isolated antibody comprises the VH sequence set forth in SEQ ID NO: 103, and the VL sequence set forth in SEQ ID NO: 106; and the human Fc region comprises wild-type, human IgGl Fc. In some embodiments, the isolated antibody comprises the VH sequence set forth in SEQ ID NO: 115, and the VL sequence set forth in SEQ ID NO: 118; and the human Fc region comprises wild-type, human IgGl Fc. In some embodiments, the isolated antibody comprises the VH sequence set forth in SEQ ID NO: 127, and the VL sequence set forth in SEQ ID NO: 130; and the human Fc region comprises wild-type, human IgGl Fc. In some embodiments, the isolated antibody comprises the VH sequence set forth in SEQ ID NO: 139, and the VL sequence set forth in SEQ ID NO: 142; and the human Fc region comprises wildtype, human IgGl Fc. In some embodiments, the isolated antibody comprises the VH sequence set forth in SEQ ID NO: 151, and the VL sequence set forth in SEQ ID NO: 154; and the human Fc region comprises wild-type, human IgGl Fc. In some embodiments, the isolated antibody comprises the VH sequence set forth in SEQ ID NO: 163, and the VL sequence set forth in SEQ ID NO: 166; and the human Fc region comprises wild-type, human IgGl Fc. In some embodiments, the isolated antibody comprises the VH sequence set forth in SEQ ID NO: 175, and the VL sequence set forth in SEQ ID NO: 178; and the human Fc region comprises wild-type, human IgGl Fc. In some embodiments, the isolated antibody comprises the VH sequence set forth in SEQ ID NO: 187, and the VL sequence set forth in SEQ ID NO: 190; and the human Fc region comprises wild-type, human IgGl Fc. In some embodiments, the isolated antibody comprises the VH sequence set forth in SEQ ID NO: 199, and the VL sequence set forth in SEQ ID NO: 202; and the human Fc region comprises wildtype, human IgGl Fc. In some embodiments, the isolated antibody comprises the VHsequence set forth in SEQ ID NO: 211, and the VL sequence set forth in SEQ ID NO: 214; and the human Fc region comprises wild-type, human IgGl Fc. In some embodiments, the isolated antibody comprises the VH sequence set forth in SEQ ID NO: 223, and the VL sequence set forth in SEQ ID NO: 226; and the human Fc region comprises wild-type, human IgGl Fc. In some embodiments, the isolated antibody comprises the VH sequence set forth in SEQ ID NO: 235, and the VL sequence set forth in SEQ ID NO: 238; and the human Fc region comprises wild-type, human IgGl Fc.

[0030] In some embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions result in increased half result in increased half-life, reduced or increased FcyR binding, reduced or increased Clq binding, reduced or increased FcRn binding, reduced or increased ADCC activity, reduced or increased ADCP activity, or reduced or increased CDC activity compared with the Fc without the one or more substitutions.

[0031] In some embodiments, the Fc region binds an Fey Receptor selected from the group consisting of: FcyRI, FcyRIIa, FcyRIIb, FcyRIIc, FcyRIIIa, and FcyRIIIb.

[0032] In some embodiments, the isolated antibody comprises a monoclonal antigen binding region.

[0033] In some embodiments, the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain binds an y377-395 epitope of the fibrin yC or fibrinogen yC domain.

[0034] In some embodiments, the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain binds to peptide comprising an amino acid sequence set forth in at least one of SEQ ID NOs: 241, and 249-253 with a KD of less than or equal to about 1, 2, 3, 4, 5, 6, 7, or 8 x 10'7to 10'9nM, as measured by a surface plasmon resonance (SPR) single cycle kinetics (SCK) or biolayer interferometry assay.

[0035] In some embodiments, the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain binds to a peptide comprising the sequence of the y377-395 epitope of the human fibrin yC or fibrinogen yC domain with a KD of less than or equal to about 10'7to 10'9nM, as measured by SPR or SCK or biolayer interferometry assay. In some embodiments, the y377-395 epitope of the human fibrin yC or fibrinogen yC domain comprises the sequence of SEQ ID NO: 241.

[0036] In some embodiments, the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain inhibits CD1 lb / CD18 (Mac-1) and CD1 lc / CD18 binding to fibrin yC or fibrinogen yC domain. In some embodiments, the isolated antibody or the means forbinding human fibrin yC or fibrinogen yC domain inhibits CD1 lb / CD18 (Mac-1) and CD1 lc / CD18 binding to fibrin yC or fibrinogen yC domain as measured by a competition assay, ELISA assay, flow cytometry, as known by a skilled artisan, or any suitable method known in the art.

[0037] In some embodiments, the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain exhibits inhibition of microglial and / or macrophage adhesion to the fibrin yC or fibrinogen yC domain. In some embodiments, the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain exhibits inhibition of microglial and / or macrophage adhesion to the fibrin yC or fibrinogen yC domain as measured by a competition assay, ELISA assay, flow cytometry, as known by a skilled artisan, or any suitable method known in the art.

[0038] In some embodiments, the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain binds human fibrin at any one of amino acid residues Lys 411, He 412, He 413, Phe 415, Asn 416, Arg 417, Leu 418, Thr 419, lie 420, and Gly 421 relative to SEQ ID NO: 265. In some embodiments, the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain binds human fibrin as measured by alanine scanning, X-ray crystallography, a peptide array, hydrogen-deuterium exchange, cryoelectron microscopy, antibody binding epitope mapping, or any suitable method known in the art.

[0039] In some embodiments, the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain binds human fibrin at least two, three, four, five, six, seven, eight, nine, or all ten of amino acid residues Lys 411, He 412, He 413, Phe 415, Asn 416, Arg 417, Leu 418, Thr 419, He 420, and Gly 421 relative to SEQ ID NO: 265. In some embodiments, the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain binds human fibrin as measured by alanine scanning, X-ray crystallography, a peptide array, hydrogen-deuterium exchange, cryo-electron microscopy, antibody binding epitope mapping, or any suitable method known in the art.

[0040] In some embodiments, the isolated antibody comprises a humanized, human, or chimeric antibody or antigen binding region. In some embodiments, the isolated antibody comprises a humanized antibody or antigen binding region.

[0041] In some embodiments, the isolated antibody comprises a heavy chain human Fc of a class selected from IgG, IgA, IgD, IgE, and IgM.

[0042] In some embodiments, the human Fc region comprises a human heavy chain constant region of the class IgG and a subclass selected from IgGl, IgG2, IgG3, and IgG4.

[0043] In some embodiments, the human Fc region comprises wild-type, human IgGl Fc.

[0044] In some embodiments, the human Fc domain comprises a sequence set forth in SEQ ID NOs: 8, 20, 32, 44, 56, 68, 80, 92, 104, 116, 128, 140, 152, 164, 176, 188, 200, 212, 224, or 236.

[0045] In some embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions results in increased result in increased half-life, reduced or increased FcyR binding, reduced or increased Clq binding, reduced or increased FcRn binding, reduced or increased ADCC activity, reduced or increased ADCP activity, or reduced or increased CDC activity compared with the Fc without the one or more substitutions.

[0046] In some embodiments, the Fc region binds an Fey Receptor selected from the group consisting of: FcyRI, FcyRIIa, FcyRIIb, FcyRIIc, FcyRIIIa, and FcyRIIIb.

[0047] In some embodiments, the the isolated antibody comprises a monoclonal antigen binding region.

[0048] In some embodiments, the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain binds to a peptide comprising an amino acid sequence set forth in at least one of SEQ ID NOs: 241, and 249-253 with a KD of less than or equal to about 1, 2, 3, 4, 5, 6, 7, or 10'7to 10'9nM, as measured by an SPR, SCK, or biolayer interferometry assay.

[0049] In some embodiments, the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain binds to a peptide comprising the sequence of the y377-395 epitope of the human fibrin yC or fibrinogen yC domain with a KD of less than or equal to about 10'7to 10'9nM, as measured by an SPR, SCK, or biolayer interferometry assay. In some embodiments, the y377-395 epitope of the human fibrin yC or fibrinogen yC domain comprises the sequence of SEQ ID NO: 241.

[0050] In some embodiments, the dosage form is administered to the subject in one or more doses, each dose selected from about 1 mg to about 10 mg to each eye.

[0051] In some embodiments, each dose is selected from about 1 mg, 2.5 mg, 5 mg, 7.5 mg, and 10 mg to each eye of the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain.

[0052] In some embodiments, each dose is about 2.5 mg to each eye of the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain. In some embodiments,each dose is about 5 mg to each eye of the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain. In some embodiments, each dose is about 7.5 mg to each eye of the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain. In some embodiments, each dose is about 10 mg to each eye of the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain. In some embodiments, each dose is about 12 mg to each eye of the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain. In some embodiments, each dose is about 15 mg to each eye of the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain.

[0053] In some embodiments, the dosage form comprises the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain at a concentration of from about 20 mg / mL to about 200 mg / mL.

[0054] In some embodiments, the dosage form comprises the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain at a concentration of greater than about 40, 60, 80, 100, 120, 160, 180, or 200 mg / mL.

[0055] In some embodiments, the dosage form comprises the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain at a concentration of about 100 mg / mL.

[0056] In some embodiments, the method comprises administering the dosage form to the subject one time per month, once every six weeks, or once every two or once every three months for one or more months or one or more doses.

[0057] In some embodiments, the method comprises administering the dosage form to the subject one time per month. In some embodiments, the method comprises administering the dosage form to the subject one time per two months. In some embodiments, the method comprises administering the dosage form to the subject one time per three months.

[0058] In some embodiments, the method comprises administering the dosage form to the subject three or more times.

[0059] In some embodiments, the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain is administered to the subject at the same dose at each administration.

[0060] In some embodiments, the method comprises administering the dosage form locally (e.g., intravitreally, subconjunctivally, retrobulbarly, and intracamerally), topically, and systemically.

[0061] In some embodiments, the method comprises administering the dosage form intravitreally.

[0062] In some embodiments, comprising administering to the subject an effective amount of one or more anti-vascular endothelial growth factor (VEGF) antibodies or antigen-binding fragments thereof.

[0063] In some embodiments, the anti-VEGF antibodies or antigen-binding fragments thereof comprise aflibercept, ranibizumab, bevacizumab efdamrofusp alfa, and faricimab-svoa and biosimilars thereof. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof is aflibercept. In some embodiments, the anti-VEGF antibody or antigenbinding fragment thereof is bevacizumab.

[0064] In some embodiments, the disorder or condition of the eye comprises retinitis pigmentosa, age-related macular degeneration, glaucoma, diabetic retinopathy, diabetic macular edema, uveitis, and retinal detachment.

[0065] In some embodiments, the disorder or condition of the eye is diabetic macular edema.

[0066] In some embodiments, the subject is a human.

[0067] Also described herein, in some embodiments, is a dosage form comprising an isolated antibody that binds human fibrin yC or fibrinogen yC domain for use in the treatment of a disorder or condition of the eye in a subject in need thereof, the use comprising administering to the subject one or more doses of the dosage form, each dose selected from about 1 mg to about 20 mg to each eye of the isolated antibody, wherein the isolated antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein, respectively: (a) CDR-H1 comprises the sequence set forth in SEQ ID NOs: 157, 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 169, 181, 193, 205, 217, or 229; (b) CDR-H2 comprises the sequence set forth in SEQ ID NOs: 158, 2, 14, 26, 38, 50, 62, 74, 86, 98, 110, 122, 134, 146, 170, 182, 194, 206, 218, or 230; (c) CDR-H3 comprises the sequence set forth in SEQ ID NOs: 159, 3, 15, 27, 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 171, 183, 195, 207, 219, or 231; (d) CDR-L1 comprises the sequence set forth in SEQ ID NOs: 160, 4, 16, 28, 40, 52, 64, 76, 88, 100, 112, 124, 136, 148, 172, 184, 196, 208, 220, or 232; (e) CDR-L2 comprises the sequence set forth in SEQ ID NOs: 161, 5, 17, 29, 41, 53, 65, 77, 89, 101, 113, 125, 137, 149, 173, 185, 197, 209, 221, or 233; and (f) CDR-L3comprises the sequence set forth in SEQ ID NOs: 162, 6, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 174, 186, 198, 210, 222, or 234.

[0068] In some embodiments, the dosage form is administered to the subject in one or more doses, each dose selected from about 1 mg to about 20 mg to each eye.

[0069] In some embodiments, each dose is selected from about 1 mg, 1.2 mg, 2.5 mg, 3.5 mg, 5 mg, 7.5 mg, 10 mg, 12 mg, and 15 mg to each eye of the isolated antibody.

[0070] In some embodiments, each dose is about 2.5 mg to each eye of the isolated antibody. In some embodiments, each dose is about 5 mg to each eye of the isolated antibody. In some embodiments, each dose is about 7.5 mg to each eye of the isolated antibody. In some embodiments, each dose is about 10 mg to each eye of the isolated antibody. In some embodiments, each dose is about 12 mg to each eye of the isolated antibody. In some embodiments, each dose is about 15 mg to each eye of the isolated antibody.

[0071] In some embodiments, the dosage form comprises the isolated antibody at a concentration of from about 20 mg / mL to about 200 mg / mL.

[0072] In some embodiments, the dosage form comprises the isolated antibody at a concentration of greater than about 40, 60, 80, 100, 120, 160, 180, or 200 mg / mL.

[0073] In some embodiments, the dosage form comprises the isolated antibody at a concentration of about 100 mg / mL.

[0074] In some embodiments, the use comprises administering the dosage form to the subject one time per month, once every six weeks, or once every two or once every three months for one or more months or one or more doses.

[0075] In some embodiments, the use comprises administering the dosage form to the subject one time per month. In some embodiments, the use comprises administering the dosage form to the subject one time per two months. In some embodiments, the use comprises administering the dosage form to the subject one time per three months.

[0076] In some embodiments, the use comprises administering the dosage form to the subject three or more times.

[0077] In some embodiments, the isolated antibody is administered to the subject at the same dose at each administration.

[0078] In some embodiments, the use comprises administering the dosage form locally (e.g., intravitreally, subconjunctivally, retrobulbarly, and intracamerally), topically, and systemically. In some embodiments, the use comprises administering the dosage form intravitreally.

[0079] In some embodiments, the use further comprises administering to the subject an effective amount of one or more anti-vascular endothelial growth factor (VEGF) antibodies or antigen-binding fragments thereof.

[0080] In some embodiments, the anti-VEGF antibodies or antigen-binding fragments thereof comprise aflibercept, ranibizumab, bevacizumab efdamrofusp alfa, and faricimab-svoa and biosimilars thereof. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof is aflibercept. In some embodiments, the anti-VEGF antibody or antigenbinding fragment thereof is bevacizumab.

[0081] In some embodiments, the disorder or condition of the eye comprises retinitis pigmentosa, age-related macular degeneration, glaucoma, diabetic retinopathy, diabetic macular edema, uveitis, and retinal detachment. In some embodiments, the disorder or condition of the eye is diabetic macular edema.

[0082] In some embodiments, the subject is a human.

[0083] Also described herein, in some embodiments, is a method of treating diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the method comprising intravitreally administering to the subject a dosage form comprising an isolated antibody that binds human fibrin yC or fibrinogen yC domain, wherein the dosage form comprises the isolated antibody at a concentration of about 100 mg / mL, and wherein the isolated antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein, respectively: (a) CDR-H1 comprises the sequence set forth in SEQ ID NO: 157; (b) CDR-H2 comprises the sequence set forth in SEQ ID NOs: 158; (c) CDR-H3 comprises the sequence set forth in SEQ ID NOs: 159; (d) CDR-L1 comprises the sequence set forth in SEQ ID NOs: 160; (e) CDR-L2 comprises the sequence set forth in SEQ ID NOs: 161; and (f) CDR-L3 comprises the sequence set forth in SEQ ID NOs: 162.

[0084] Also described herein, in some embodiments, is a method of treating diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the method comprising intravitreally administering to the subject a dosage form comprising a means for binding human fibrin yC or fibrinogen yC domain, wherein the dosage form comprises the means for binding human fibrin yC or fibrinogen yC domain at a concentration of about 100 mg / mL.

[0085] In some embodiments, the method comprises administering the dosage form to the subject one, two, three, or four times per month for one or more doses or one or more months (e.g., three months).

[0086] In some embodiments, the method comprises administering the dosage form to the subject one time per month.

[0087] In some embodiments, the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain is administered to the subject at the same dose at each administration.

[0088] In some embodiments, the method comprises administering the dosage form to the subject for three or more months. In some embodiments, the method comprises administering the dosage form to the subject for three months.

[0089] In some embodiments, the subject is a human.

[0090] Also described herein, in some embodiments, is a method of treating diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the method comprising intravitreally administering to the subject one or more doses of a dosage form comprising an isolated antibody that binds human fibrin yC or fibrinogen yC domain, each dose selected from about 1.2 mg, about 3.5 mg, and about 10 mg to each eye of the isolated antibody, wherein the isolated antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein, respectively: (a) CDR-H1 comprises the sequence set forth in SEQ ID NO: 157; (b) CDR-H2 comprises the sequence set forth in SEQ ID NOs: 158; (c) CDR-H3 comprises the sequence set forth in SEQ ID NOs: 159; (d) CDR-L1 comprises the sequence set forth in SEQ ID NOs: 160; (e) CDR-L2 comprises the sequence set forth in SEQ ID NOs: 161; and (f) CDR-L3 comprises the sequence set forth in SEQ ID NOs: 162.

[0091] Also described herein, in some embodiments, is a method of treating diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the method comprising intravitreally administering to the subject one or more doses of a dosage form comprising a means for binding human fibrin yC or fibrinogen yC domain, each dose selected from about 1.2 mg, about 3.5 mg, and about 10 mg to each eye of the means for binding human fibrin yC or fibrinogen yC domain.

[0092] In some embodiments, the method comprises administering the dosage form to the subject one, two, three, or four times per month for one or more doses or one or more months (e.g., three months).

[0093] In some embodiments, the method comprises administering the dosage form to the subject one time per month.

[0094] In some embodiments, the isolated antibody or the means for binding human fibrin yC or fibrinogen yC domain is administered to the subject at the same dose at each administration.

[0095] In some embodiments, the method comprises administering the dosage form to the subject for three or more months. In some embodiments, the method comprises administering the dosage form to the subject for three months.

[0096] In some embodiments, the subject is a human.

[0097] Also described herein, in some embodiments, is a dosage form comprising an isolated antibody that binds human fibrin yC or fibrinogen yC domain for use in the treatment of diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the use comprising intravitreally administering to the subject the dosage form, wherein the dosage form comprises the isolated antibody at a concentration of about 100 mg / mL, and wherein the isolated antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein, respectively: (a) CDR-H1 comprises the sequence set forth in SEQ ID NO: 157; (b) CDR-H2 comprises the sequence set forth in SEQ ID NOs: 158; (c) CDR-H3 comprises the sequence set forth in SEQ ID NOs: 159; (d) CDR-L1 comprises the sequence set forth in SEQ ID NOs: 160; (e) CDR-L2 comprises the sequence set forth in SEQ ID NOs: 161; and (f) CDR-L3 comprises the sequence set forth in SEQ ID NOs: 162.

[0098] In some embodiments, the use comprises administering the dosage form to the subject one, two, three, or four times per month for one or doses or one or more months (e.g., three months).

[0099] In some embodiments, the use comprises administering the dosage form to the subject two times per month.

[0100] In some embodiments, the isolated antibody is administered to the subject at the same dose at each administration.

[0101] In some embodiments, the use comprises administering the dosage form to the subject for three or more months. In some embodiments, the use comprises administering the dosage form to the subject for three months.

[0102] Also described herein, in some embodiments, is a dosage form comprising an isolated antibody that binds human fibrin yC or fibrinogen yC domain for use in the treatment of diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the use comprising intravitreally administering to the subject one or more doses of the dosage form, each dose selected from about 1.2 mg, about 3.5 mg, and about 10 mg to each eye of the isolated antibody, wherein the isolated antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein, respectively: (a) CDR-H1 comprises the sequence set forth in SEQ ID NO: 157; (b) CDR-H2 comprises the sequence set forth in SEQ ID NOs: 158; (c) CDR-H3 comprises the sequence set forth in SEQ ID NOs: 159; (d) CDR-L1 comprises the sequence set forth in SEQ ID NOs: 160; (e) CDR-L2 comprises the sequence set forth in SEQ ID NOs: 161; and (f) CDR-L3 comprises the sequence set forth in SEQ ID NOs: 162.

[0103] In some embodiments, the use comprises administering the dosage form to the subject one, two, three, or four times per month for one or more doses or one or more months (e.g., three months).

[0104] In some embodiments, the use comprises administering the dosage form to the subject two times per month.

[0105] In some embodiments, the isolated antibody is administered to the subject at the same dose at each administration.

[0106] In some embodiments, the use comprises administering the dosage form to the subject for three or more months. In some embodiments, the use comprises administering the dosage form to the subject for three months.

[0107] In some embodiments, the subject is a human.BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0108] These and other features, embodiments, and advantages of the present disclosure will become better understood with regard to the following description, and accompanying drawings, where:

[0109] FIG. 1 is a graph depicting the uveitis clinical score of rats administered intravitreally isotype control, murinized antibody clone 60143-with Fc stabilization LALA mutations (mADI-60143 LALA; low dose = 10 pg / eye; high dose = 50 pg / eye), positive control FTY-720 (administered by oral gavage at a dose of 0.3 mg / kg) and naive mice with no experimental autoimmune encephalomyelitis (EAE) induction.

[0110] FIG. 2 is a graph showing vascular leakage via quantitative fluorescein angiography (qFA) in rats treated with the anti-VEGF antigen binding construct Eylea (aflibercept) and mADI-60143 LALA at the indicated concentrations. qFA images were recorded at 4- and 6-min. post-fluorescein injection and differences in the integrated density (IntDen Diff) between the two times post-injection were calculated as a readout of vascular leakage.

[0111] FIG. 3 is a graph showing choroidal neovascularization (CNV) lesion area in rats treated with the anti-VEGF antigen binding construct Eylea (aflibercept) and mADI-60143 LALA at the indicated concentrations.

[0112] FIG. 4 is a set of graphs showing vascular leakage via qFA in rats treated with ADI-60143 LALA, an anti-VEGF antibody (bevacizumab or aflibercept), or an isotype control. qFA images were recorded at 4- and 6-min. post-fluorescein injection and differences in the integrated density (IntDen Diff) between the two times post-injection were calculated as a readout of vascular leakage. Measurements were taken at Day 7, 14, and 28 post laser- induced choroidal neovascularization (LCNV). Results shown are individual eyes, depicting the mean ± 95% confidence interval, and analyzed by one-way ANOVA, with Dunnett’s multiple comparison to the isotype control.

[0113] FIG. 5 is set of graphs showing CNV lesion area in rats treated with the anti- VEGF antigen binding construct Eylea (aflibercept), mADI-60143 LALA, ADI-60143 LALA, or an isotype control at the indicated concentrations at Day 7, 14, and 28 post LCNV.

[0114] FIG. 6 is a graph showing vascular leakage via qFA in rats having (STZ)-induced diabetic retinopathy and treated with ADI-60143 LALA or an isotype control (“STZ Control”). qFA images were recorded at 4- and 6-min. post-fluorescein injection and differences in the integrated density (IntDen Diff) between the two times post-injection were calculated as a readout of vascular leakage.

[0115] FIG. 7 is a graph showing vascular leakage via qFA in the rats described in FIG. 4 intravitreally treated with two treatments of ADI-60143 LALA at 8 pg / eye (low dose), 16pg / eye (medium dose), or 50 pg / eye (high dose) on days 14 and 28. Results shown are individual eyes, mean ± 95% confidence interval, unpaired t-test for each comparison.

[0116] FIG. 8 is a schematic showing a representative Phase l / 2a study design to evaluate the safety and biological activity of intravitreal (IVT) ADI-60143 LALA in diabetic retinopathy and diabetic macular edema (DME). Abbreviations: MTD, maximum tolerated dose; min, minimum; DSMC, data safety monitoring committee; Q4W, once every four weeks.

[0117] FIG. 9 is a schematic showing a representative Phase 1 study design to evaluate the safety and biological activity of intravitreal (IVT) ADI-60143 LALA in diabetic macular edema (DME). Abbreviations: IVT, intravitreally; Q4W, once every four weeks.

[0118] FIG. 10A is a graph showing a non-compartmental pharmacokinetic (PK) analysis of the concentration of ADI-60143 LALA over time in rabbits, following 1.5 mg / eye intravitreal administration, in the aqueous humor, choroid / retinal pigment epithelium (RPE), retina, and vitreous humor.

[0119] FIG. 10B is a graph showing a three-compartment pharmacokinetic (PK) analysis of the concentration of ADI-60143 LALA over time in rabbits, following 1.5 mg / eye intravitreal administration, in the aqueous humor, choroid / retinal pigment epithelium (RPE), retina, and vitreous humor.

[0120] FIG. 11 is a graph showing an analysis of the concentration of ADI-60143 LALA over time in the vitreous humor and retina of humans, following 10 mg / eye intravitreal (IVT) injection Q4W. Abbreviation: KD, equilibrium dissociation constant.

[0121] FIG. 12 is a graph showing choroidal neovascularization (CNV) lesion area in mice treated with the a control IgG, anti-VEGF antigen binding construct Eylea (aflibercept), or ADI-60143 LALA.DETAILED DESCRIPTIONDefinitions

[0122] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understoodand commonly employed using conventional methodologies by those skilled in the art, such as, for example, the widely utilized molecular cloning methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 4thed. (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer-defined protocols and conditions unless otherwise noted.

[0123] As used herein, the singular form “a,” “an,” and “the” includes plural references unless indicated otherwise.

[0124] It is understood that embodiments and embodiments of the disclosure described herein include “comprising,” “consisting,” and “consisting essentially of’ embodiments and embodiments.

[0125] For all compositions described herein, and all methods using a composition described herein, the compositions can either comprise the listed components or steps, or can “consist essentially of’ the listed components or steps. When a composition is described as “consisting essentially of’ the listed components, the composition contains the components listed, and may contain other components which do not substantially affect the condition being treated, but do not contain any other components which substantially affect the condition being treated other than those components expressly listed; or, if the composition does contain extra components other than those listed which substantially affect the condition being treated, the composition does not contain a sufficient concentration or amount of the extra components to substantially affect the condition being treated. When a method is described as “consisting essentially of’ the listed steps, the method contains the steps listed, and may contain other steps that do not substantially affect the condition being treated, but the method does not contain any other steps which substantially affect the condition being treated other than those steps expressly listed. As a non-limiting specific example, when a composition is described as ‘consisting essentially of a component, the composition may additionally contain any amount of pharmaceutically acceptable carriers, vehicles, or diluents and other such components which do not substantially affect the condition being treated.

[0126] The term “vector,” as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a selfreplicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expressionof nucleic acids to which they are operatively linked. Such vectors are referred to herein as “expression vectors.”

[0127] An “effective amount” or “therapeutically effective amount” as used herein refers to an amount of therapeutic compound, such as an anti-fibrin antibody, administered to an individual, either as a single dose or as part of a series of doses, which is effective to produce or contribute to a desired therapeutic effect, either alone or in combination with another therapeutic modality. Examples of a desired therapeutic effect is enhancing an immune response, slowing or delaying tumor development; stabilization of disease; and amelioration of one or more symptoms. An effective amount may be given in one or more dosages.

[0128] The term “treating” (and variations thereof such as “treat” or “treatment”) refers to clinical intervention in an attempt to alter the natural course of a disease or condition in a subject in need thereof. Treatment can be performed during the course of clinical pathology. Desirable effects of treatment include preventing recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. None of these terms require the supervision of medical personnel.

[0129] The term “sufficient amount” means an amount sufficient to produce a desired effect, e.g., an amount sufficient to modulate an immune response in a subject.

[0130] As used herein, the terms “subject” or “individual” mean a mammalian subject. Exemplary subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, and sheep.

[0131] The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic or diagnostic products (e.g., kits) that contain information about the indications, usage, dosage, administration, combination therapy, contraindications, and / or warnings concerning the use of such therapeutic or diagnostic products.

[0132] The term “pharmaceutical composition” refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective in treating a subject, and which contains no additional components which are unacceptably toxic to the subject in the amounts provided in the pharmaceutical composition.

[0133] The terms “co-administration,” “co-administer,” and “in combination with” include the administration of two or more therapeutic agents either simultaneously, concurrently, or sequentially within no specific time limits.

[0134] The terms “modulate” and “modulation” refer to reducing or inhibiting or, alternatively, activating or increasing, a recited variable.

[0135] The terms “increase” and “activate” refer to an increase of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or greater in a recited variable.

[0136] The terms “reduce” and “inhibit” refer to a decrease of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or greater in a recited variable.

[0137] The term “about” indicates and encompasses an indicated value and a range above and below that value. For example, the term “about” indicates the designated value ± 10%, ± 5%, or ± 1%. Where applicable, the term “about” indicates the designated value(s) ± one standard deviation of that value(s).

[0138] The term “optionally” is meant, when used sequentially, to include from one to all of the enumerated combinations and contemplates all sub-combinations.

[0139] The term “amino acid” refers to the twenty common naturally occurring amino acids. Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C); glutamic acid (Glu; E), glutamine (Gin; Q), Glycine (Gly; G); histidine (His; H), isoleucine (He; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Vai; V).

[0140] The term “antibody” is used herein in its broadest sense and includes covers monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multi-specific antibodies (e.g., bispecific antibodies), and antibody fragments e.g., single domain antibodies, diabodies, knobs-into-hole antibodies, scFv, scFv dimers, BsFv, dsFv, a(dsFv)2, dsFv-dsFv', Fv fragments, Fab, Fab', F(ab')2, ds diabodies, minibodies, nanobodies, domain antibodies, and bivalent domain antibodies so long as they exhibit the desired biological activity.

[0141] A “fibrin antibody,” “anti-fibrin antibody,” or “fibrin-specific antibody” is an antibody, as provided herein, which specifically binds to the antigen fibrin. In some embodiments, the antibody binds the inflammatory domain of fibrin. In some embodiments, afibrin antibody provided herein binds to an epitope of fibrin that is conserved between or among fibrin proteins from different species.

[0142] The term “epitope” means a portion of an antigen that specifically binds to an antibody.

[0143] The term “antigen -binding region” means the portion of an antibody that is capable of specifically binding to an antigen or epitope.

[0144] The term “human antibody” refers to an antibody which possesses an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies.

[0145] The term “humanized antibody” refers to a protein having a sequence that differs from the sequence of an antibody derived from a non-human species by one or more amino acid substitutions, deletions, and / or additions, such that the humanized antibody is less likely to induce an immune response, and / or induces a less severe immune response, as compared to the non-human species antibody, when it is administered to a human subject.

[0146] The term “substantially purified” refers to a construct described herein, or variant thereof that may be substantially or essentially free of components that normally accompany or interact with the protein as found in its naturally occurring environment, i.e. a native cell, or host cell in the case of recombinantly produced hetero-multimer that in some embodiments, is substantially free of cellular material includes preparations of protein having less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% (by dry weight) of contaminating protein.

[0147] The term percent “identity,” in the context of two or more nucleic acid or polypeptide sequences, refer to two or more sequences or subsequences that have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned for maximum correspondence, as measured using one of the sequence comparison algorithms described below (e.g., using publicly available computer software such as BLAST, BLASTP, BLASTN, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE software or other algorithms available to persons of skill) or by visual inspection. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (ncbi.nlm.nih.gov). Those skilledin the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Depending on the application, the percent “identity” can exist over a region of the sequence being compared, e.g., over a functional domain, or, alternatively, exist over the full length of the two sequences to be compared.

[0148] For sequence comparison, typically one sequence acts as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.

[0149] Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (see generally Ausubel et al., infra).

[0150] Ranges recited herein are understood to be shorthand for all of the values within the range, inclusive of the recited endpoints. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50.

[0151] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.Anti-Fibrin Antibodies

[0152] The present application provides dosage forms (e.g., pharmaceutical formulations) comprising anti-fibrin antibodies described herein.

[0153] In some embodiments, the anti-fibrin antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light(VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein, respectively: CDR-H1 comprises the sequence set forth in SEQ ID NOs: 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181, 193, 205, 217, or 229; CDR-H2 comprises the sequence set forth in SEQ ID NOs: 2, 14, 26, 38, 50, 62, 74, 86, 98, 110, 122, 134, 146, 158, 170, 182, 194, 206, 218, or 230; CDR-H3 comprises the sequence set forth in SEQ ID NOs: 3, 15, 27, 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 159, 171, 183, 195, 207, 219, or 231; CDR-L1 comprises the sequence set forth in SEQ ID NOs: 4, 16, 28, 40, 52, 64, 76, 88, 100, 112, 124, 136, 148, 160, 172, 184, 196, 208, 220, or 232; CDR-L2 comprises the sequence set forth in SEQ ID NOs: 5, 17, 29, 41, 53, 65, 77, 89, 101, 113, 125, 137, 149, 161, 173, 185, 197, 209, 221, or 233; and CDR-L3 comprises the sequence set forth in SEQ ID NOs: 6, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, or 234. As used herein, “respectively” means that when multiple lists are referenced, each list having a number of elements, the combination is obtained by grouping the 1st, 2nd, 3rd, etc. element from each list together. For example, when list 1 includes elements a, b, and c; and list 2 includes elements d, e, and f, the respective combinations are a and d; b and e; and c and f.

[0154] In some embodiments, the anti-fibrin antibody comprises a VH sequence selected from a sequence set forth in any one of SEQ ID NOs: 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 163, 175, 187, 199, 211, 223, or 235.

[0155] In some embodiments, the anti-fibrin antibody comprises a VL sequence selected from a sequence set forth in SEQ ID NOs: 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 166, 178, 190, 202, 214, 226, or 238.

[0156] In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 157, a CDR-H2 of SEQ ID NO: 158, and a CDR-H3 of SEQ ID NO: 159, and a VL comprising a CDR-L1 of SEQ ID NO: 160, a CDR-L2 of SEQ ID NO: 161, and a CDR-L3 of SEQ ID NO: 162. In some embodiments, the anti-fibrin antibody comprises a VH having the sequence set forth in SEQ ID NO: 163. In some embodiments, the anti-fibrin antibody comprises a VL having the sequence set forth in SEQ ID NO: 166.

[0157] In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 1, a CDR-H2 of SEQ ID NO: 2, and a CDR-H3 of SEQ ID NO: 24, and a VL comprising a CDR-L1 of SEQ ID NO: 4, a CDR-L2 of SEQ ID NO: 5, and a CDR- L3 of SEQ ID NO: 6. In some embodiments, the anti-fibrin antibody comprises a VH havingthe sequence set forth in SEQ ID NO: 7. In some embodiments, the anti-fibrin antibody comprises a VL having the sequence set forth in SEQ ID NO: 10.

[0158] In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 13, a CDR-H2 of SEQ ID NO: 14, and a CDR-H3 of SEQ ID NO: 15, and a VL comprising a CDR-L1 of SEQ ID NO: 16, a CDR-L2 of SEQ ID NO: 17, and a CDR-L3 of SEQ ID NO: 18. In some embodiments, the anti-fibrin antibody comprises a VH having the sequence set forth in SEQ ID NO: 19. In some embodiments, the anti-fibrin antibody comprises a VL having the sequence set forth in SEQ ID NO: 22.

[0159] In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 25, a CDR-H2 of SEQ ID NO: 26, and a CDR-H3 of SEQ ID NO: 27, and a VL comprising a CDR-L1 of SEQ ID NO: 28, a CDR-L2 of SEQ ID NO: 29, and a CDR-L3 of SEQ ID NO: 30. In some embodiments, the anti-fibrin antibody comprises a VH having the sequence set forth in SEQ ID NO: 31. In some embodiments, the anti-fibrin antibody comprises a VL having the sequence set forth in SEQ ID NO: 34.

[0160] In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 37, a CDR-H2 of SEQ ID NO: 38, and a CDR-H3 of SEQ ID NO: 39, and a VL comprising a CDR-L1 of SEQ ID NO: 40, a CDR-L2 of SEQ ID NO: 41, and a CDR-L3 of SEQ ID NO: 42. In some embodiments, the anti-fibrin antibody comprises a VH having the sequence set forth in SEQ ID NO: 43. In some embodiments, the anti-fibrin antibody comprises a VL having the sequence set forth in SEQ ID NO: 46.

[0161] In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 49, a CDR-H2 of SEQ ID NO: 50, and a CDR-H3 of SEQ ID NO: 51, and a VL comprising a CDR-L1 of SEQ ID NO: 52, a CDR-L2 of SEQ ID NO: 53, and a CDR-L3 of SEQ ID NO: 54. In some embodiments, the anti-fibrin antibody comprises a VH having the sequence set forth in SEQ ID NO: 55. In some embodiments, the anti-fibrin antibody comprises a VL having the sequence set forth in SEQ ID NO: 58.

[0162] In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 61, a CDR-H2 of SEQ ID NO: 62, and a CDR-H3 of SEQ ID NO: 63, and a VL comprising a CDR-L1 of SEQ ID NO: 64, a CDR-L2 of SEQ ID NO: 65, and a CDR-L3 of SEQ ID NO: 66. In some embodiments, the anti-fibrin antibody comprises a VH having the sequence set forth in SEQ ID NO: 67. In some embodiments, the anti-fibrin antibody comprises a VL having the sequence set forth in SEQ ID NO: 70.

[0163] In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 73, a CDR-H2 of SEQ ID NO: 74, and a CDR-H3 of SEQ ID NO: 75, and a VL comprising a CDR-L1 of SEQ ID NO: 76, a CDR-L2 of SEQ ID NO: 77, and a CDR-L3 of SEQ ID NO: 78. In some embodiments, the anti-fibrin antibody comprises a VH having the sequence set forth in SEQ ID NO: 79. In some embodiments, the anti-fibrin antibody comprises a VL having the sequence set forth in SEQ ID NO: 82.

[0164] In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 85, a CDR-H2 of SEQ ID NO: 86, and a CDR-H3 of SEQ ID NO: 87, and a VL comprising a CDR-L1 of SEQ ID NO: 88, a CDR-L2 of SEQ ID NO: 89, and a CDR-L3 of SEQ ID NO: 90. In some embodiments, the anti-fibrin antibody comprises a VH having the sequence set forth in SEQ ID NO: 91. In some embodiments, the anti-fibrin antibody comprises a VL having the sequence set forth in SEQ ID NO: 94.

[0165] In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 97, a CDR-H2 of SEQ ID NO: 98, and a CDR-H3 of SEQ ID NO: 99, and a VL comprising a CDR-L1 of SEQ ID NO: 100, a CDR-L2 of SEQ ID NO: 101, and a CDR-L3 of SEQ ID NO: 102. In some embodiments, the anti-fibrin antibody comprises a VH having the sequence set forth in SEQ ID NO: 103. In some embodiments, the anti-fibrin antibody comprises a VL having the sequence set forth in SEQ ID NO: 106.

[0166] In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 109, a CDR-H2 of SEQ ID NO: 110, and a CDR-H3 of SEQ ID NO: 111, and a VL comprising a CDR-L1 of SEQ ID NO: 112, a CDR-L2 of SEQ ID NO: 113, and a CDR-L3 of SEQ ID NO: 114. In some embodiments, the anti-fibrin antibody comprises a VH having the sequence set forth in SEQ ID NO: 115. In some embodiments, the anti-fibrin antibody comprises a VL having the sequence set forth in SEQ ID NO: 118.

[0167] In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 121, a CDR-H2 of SEQ ID NO: 122, and a CDR-H3 of SEQ ID NO: 123, and a VL comprising a CDR-L1 of SEQ ID NO: 124, a CDR-L2 of SEQ ID NO: 125, and a CDR-L3 of SEQ ID NO: 126. In some embodiments, the anti-fibrin antibody comprises a VH having the sequence set forth in SEQ ID NO: 127. In some embodiments, the anti-fibrin antibody comprises a VL having the sequence set forth in SEQ ID NO: 130.

[0168] In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 133, a CDR-H2 of SEQ ID NO: 134, and a CDR-H3 of SEQ ID NO: 135, and a VL comprising a CDR-L1 of SEQ ID NO: 136, a CDR-L2 of SEQ ID NO:137, and a CDR-L3 of SEQ ID NO: 138. In some embodiments, the anti-fibrin antibody comprises a VH having the sequence set forth in SEQ ID NO: 139. In some embodiments, the anti-fibrin antibody comprises a VL having the sequence set forth in SEQ ID NO: 142.

[0169] In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 145, a CDR-H2 of SEQ ID NO: 146, and a CDR-H3 of SEQ ID NO: 147, and a VL comprising a CDR-L1 of SEQ ID NO: 148, a CDR-L2 of SEQ ID NO: 149, and a CDR-L3 of SEQ ID NO: 150. In some embodiments, the anti-fibrin antibody comprises a VH having the sequence set forth in SEQ ID NO: 151. In some embodiments, the anti-fibrin antibody comprises a VL having the sequence set forth in SEQ ID NO: 154.

[0170] In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 169, a CDR-H2 of SEQ ID NO: 170, and a CDR-H3 of SEQ ID NO: 171, and a VL comprising a CDR-L1 of SEQ ID NO: 172, a CDR-L2 of SEQ ID NO: 173, and a CDR-L3 of SEQ ID NO: 174. In some embodiments, the anti-fibrin antibody comprises a VH having the sequence set forth in SEQ ID NO: 175. In some embodiments, the anti-fibrin antibody comprises a VL having the sequence set forth in SEQ ID NO: 178.

[0171] In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 181, a CDR-H2 of SEQ ID NO: 182, and a CDR-H3 of SEQ ID NO: 183, and a VL comprising a CDR-L1 of SEQ ID NO: 184, a CDR-L2 of SEQ ID NO: 185, and a CDR-L3 of SEQ ID NO: 186. In some embodiments, the anti-fibrin antibody comprises a VH having the sequence set forth in SEQ ID NO: 187. In some embodiments, the anti-fibrin antibody comprises a VL having the sequence set forth in SEQ ID NO: 190.

[0172] In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 193, a CDR-H2 of SEQ ID NO: 194, and a CDR-H3 of SEQ ID NO: 195, and a VL comprising a CDR-L1 of SEQ ID NO: 196, a CDR-L2 of SEQ ID NO: 197, and a CDR-L3 of SEQ ID NO: 198. In some embodiments, the anti-fibrin antibody comprises a VH having the sequence set forth in SEQ ID NO: 199. In some embodiments, the anti-fibrin antibody comprises a VL having the sequence set forth in SEQ ID NO: 202.

[0173] In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 205, a CDR-H2 of SEQ ID NO: 206, and a CDR-H3 of SEQ ID NO: 207, and a VL comprising a CDR-L1 of SEQ ID NO: 208, a CDR-L2 of SEQ ID NO: 209, and a CDR-L3 of SEQ ID NO: 210. In some embodiments, the anti-fibrin antibody comprises a VH having the sequence set forth in SEQ ID NO: 211. In some embodiments, the anti-fibrin antibody comprises a VL having the sequence set forth in SEQ ID NO: 214.

[0174] In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 217, a CDR-H2 of SEQ ID NO: 218, and a CDR-H3 of SEQ ID NO: 219, and a VL comprising a CDR-L1 of SEQ ID NO: 220, a CDR-L2 of SEQ ID NO: 221, and a CDR-L3 of SEQ ID NO: 222. In some embodiments, the anti-fibrin antibody comprises a VH having the sequence set forth in SEQ ID NO: 223. In some embodiments, the anti-fibrin antibody comprises a VL having the sequence set forth in SEQ ID NO: 226.

[0175] In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 229, a CDR-H2 of SEQ ID NO: 230, and a CDR-H3 of SEQ ID NO: 231, and a VL comprising a CDR-L1 of SEQ ID NO: 232, a CDR-L2 of SEQ ID NO: 233, and a CDR-L3 of SEQ ID NO: 234. In some embodiments, the anti-fibrin antibody comprises a VH having the sequence set forth in SEQ ID NO: 235. In some embodiments, the anti-fibrin antibody comprises a VL having the sequence set forth in SEQ ID NO: 238.

[0176] In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 1, a CDR-H2 of SEQ ID NO: 2, and a CDR-H3 of SEQ ID NO: 25, and a VL comprising a CDR-L1 of SEQ ID NO: 4, a CDR-L2 of SEQ ID NO: 5, and a CDR- L3 of SEQ ID NO: 6. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 1, a CDR-H2 of SEQ ID NO: 2, and a CDR-H3 of SEQ ID NO: 26, and a VL comprising a CDR-L1 of SEQ ID NO: 4, a CDR-L2 of SEQ ID NO: 5, and a CDR-L3 of SEQ ID NO: 6. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 1, a CDR-H2 of SEQ ID NO: 2, and a CDR-H3 of SEQ ID NO: 27, and a VL comprising a CDR-L1 of SEQ ID NO: 4, a CDR-L2 of SEQ ID NO: 5, and a CDR-L3 of SEQ ID NO: 6. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 1, a CDR-H2 of SEQ ID NO: 2, and a CDR-H3 of SEQ ID NO: 28, and a VL comprising a CDR-L1 of SEQ ID NO: 4, a CDR-L2 of SEQ ID NO: 5, and a CDR-L3 of SEQ ID NO: 6. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 1, a CDR-H2 of SEQ ID NO: 2, and a CDR-H3 of SEQ ID NO: 29, and a VL comprising a CDR-L1 of SEQ ID NO: 4, a CDR-L2 of SEQ ID NO: 5, and a CDR-L3 of SEQ ID NO: 6. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 1, a CDR-H2 of SEQ ID NO: 2, and a CDR-H3 of SEQ ID NO: 30, and a VL comprising a CDR-L1 of SEQ ID NO: 4, a CDR-L2 of SEQ ID NO: 5, and a CDR-L3 of SEQ ID NO: 6.

[0177] The amino acid sequence boundaries of a CDR can be determined by one of skill in the art using any of a number of known numbering schemes, including those described by Kabat et al., supra (“Kabat” numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol..273:927-948 (“Chothia” numbering scheme); MacCallum et al., 1996, J. Mol. Biol. 2621132- 745 (“Contact” numbering scheme); Lefranc et al., Dev. Comp. Immunol., 2003, 27:55-77 (“IMGT” numbering scheme); and Honegge and Pliickthun, J. Mol. Biol., 2001, 309:657-70 (“AHo” numbering scheme); each of which is incorporated by reference in its entirety.

[0178] Table 1 provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR- H2, and CDR-H3 as identified by the Kabat and Chothia schemes. For CDR-H1, residue numbering is provided using both the Kabat and Chothia numbering schemes.

[0179] CDRs may be assigned, for example, using antibody numbering software, such as Abnum, available at www.bioinf.org.uk / abs / abnum / , and described in Abhinandan and Martin, Immunology, 2008, 45:3832-3839, incorporated by reference in its entirety.Table 1. Residues in CDRs according to Kabat and Chothia numbering schemes.* The C-terminus of CDR-H1, when numbered using the Kabat numbering convention, varies between H32 and H34, depending on the length of the CDR.

[0180] The “EU numbering scheme” is generally used when referring to a residue in an antibody heavy chain constant region (e.g., as reported in Kabat et al., supra). Unless stated otherwise, the EU numbering scheme is used to refer to residues in antibody heavy chain constant regions described herein.

[0181] One example of an antigen-binding region is an antigen-binding region formed by a VH-VL dimer of an antibody. Another example of an antigen-binding region is an antigenbinding region formed by diversification of certain loops from the tenth fibronectin type III domain of an Adnectin. An antigen-binding region can include CDRs 1, 2, and 3 from a heavy chain in that order; and CDRs 1, 2, and 3 from a light chain in that order.

[0182] Epitopes frequently consist of surface-accessible amino acid residues and / or sugar side chains and may have specific three-dimensional structural characteristics, as well asspecific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter may be lost in the presence of denaturing solvents. An epitope may comprise amino acid residues that are directly involved in the binding, and other amino acid residues, which are not directly involved in the binding. The epitope to which an antibody binds can be determined using known techniques for epitope determination such as, for example, testing for antibody binding to fibrin variants with different point-mutations, or to chimeric fibrin variants.

[0183] In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence selected from SEQ ID NOs: 163, 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 175, 187, 199, 211, 223, 235, and 254. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence of SEQ ID NO: 163. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence of SEQ ID NO: 7. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence of SEQ ID NO: 19. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence of SEQ ID NO: 31. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence of SEQ ID NO: 43. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence of SEQ ID NO: 55. In some embodiments, an anti- fibrin antibody provided herein comprises a VH sequence of SEQ ID NO: 67. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence of SEQ ID NO: 79. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence of SEQ ID NO: 91. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence of SEQ ID NO: 103. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence of SEQ ID NO: 115. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence of SEQ ID NO: 127. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence of SEQ ID NO: 139. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence of SEQ ID NO: 151. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence of SEQ ID NO: 175. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence of SEQ ID NO: 187. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence of SEQ ID NO: 199. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence of SEQ ID NO: 211. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence of SEQ ID NO: 223. In some embodiments, an anti-fibrin antibody provided hereincomprises a VH sequence of SEQ ID NO: 235. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence of SEQ ID NO: 254.

[0184] In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence having at least about 50%, 60%, 70%, 80%, 90%, 95%, or 99% identity to an illustrative VH sequence provided in SEQ ID NOs: 163, 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 175, 187, 199, 211, 223, 235, and 254. In some embodiments, an anti- fibrin antibody provided herein comprises a VH sequence provided in SEQ ID NOs: 163, 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 175, 187, 199, 211, 223, 235, and 254, with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and are, for example, isolated de novo according to the methods provided herein for obtaining antibodies.

[0185] In some embodiments, an anti-fibrin antibody provided herein comprises a VL sequence selected from any one of SEQ ID NOs: 166, 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 178, 190, 202, 214, 226, 238, and 255. In some embodiments, an anti-fibrin antibody provided herein comprises a VL sequence of SEQ ID NO: 166. In some embodiments, an anti-fibrin antibody provided herein comprises a VL sequence of SEQ ID NO: 10. In some embodiments, an anti-fibrin antibody provided herein comprises a VL sequence of SEQ ID NO: 22. In some embodiments, an anti-fibrin antibody provided herein comprises a VL sequence of SEQ ID NO: 34. In some embodiments, an anti-fibrin antibody provided herein comprises a VL sequence of SEQ ID NO: 46. In some embodiments, an anti- fibrin antibody provided herein comprises a VL sequence of SEQ ID NO: 58. In some embodiments, an anti-fibrin antibody provided herein comprises a VL sequence of SEQ ID NO: 70. In some embodiments, an anti-fibrin antibody provided herein comprises a VL sequence of SEQ ID NO: 82. In some embodiments, an anti-fibrin antibody provided herein comprises a VL sequence of SEQ ID NO: 94. In some embodiments, an anti-fibrin antibody provided herein comprises a VL sequence of SEQ ID NO: 106. In some embodiments, an anti-fibrin antibody provided herein comprises a VL sequence of SEQ ID NO: 118. In someembodiments, an anti-fibrin antibody provided herein comprises a VL sequence of SEQ ID NO: 130. In some embodiments, an anti-fibrin antibody provided herein comprises a VL sequence of SEQ ID NO: 142. In some embodiments, an anti-fibrin antibody provided herein comprises a VL sequence of SEQ ID NO: 154. In some embodiments, an anti-fibrin antibody provided herein comprises a VL sequence of SEQ ID NO: 178. In some embodiments, an anti-fibrin antibody provided herein comprises a VL sequence of SEQ ID NO: 190. In some embodiments, an anti-fibrin antibody provided herein comprises a VL sequence of SEQ ID NO: 202. In some embodiments, an anti-fibrin antibody provided herein comprises a VL sequence of SEQ ID NO: 214. In some embodiments, an anti-fibrin antibody provided herein comprises a VL sequence of SEQ ID NO: 226. In some embodiments, an anti-fibrin antibody provided herein comprises a VL sequence of SEQ ID NO: 238. In some embodiments, an anti-fibrin antibody provided herein comprises a VL sequence of SEQ ID NO: 255.

[0186] In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence selected from SEQ ID NOs: 163, 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 175, 187, 199, 211, 223, 235, and 254; and a VL sequence provided in SEQ ID NOs: 166, 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 178, 190, 202, 214, 226, 238, and 255.

[0187] In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence set forth in SEQ ID NO: 163 and a VL sequence set forth in any one of SEQ ID NOs: 166, 321, or 324. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence set forth in SEQ ID NO: 163 and a VL sequence set forth in SEQ ID NO: 166. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 10. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence set forth in SEQ ID NO: 19 and a VL sequence set forth in SEQ ID NO: 22. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence set forth in SEQ ID NO: 31 and a VL sequence set forth in SEQ ID NO: 34. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence set forth in SEQ ID NO: 43 and a VL sequence set forth in SEQ ID NO: 46. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence set forth in SEQ ID NO: 55 and a VL sequence set forth in SEQ ID NO: 58. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence set forth in SEQ ID NO: 67 and a VL sequence set forth in SEQ ID NO: 70. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence setforth in SEQ ID NO: 79 and a VL sequence set forth in SEQ ID NO: 82. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence set forth in SEQ ID NO: 91 and a VL sequence set forth in SEQ ID NO: 94. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence set forth in SEQ ID NO: 103 and a VL sequence set forth in SEQ ID NO: 106. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence set forth in SEQ ID NO: 115 and a VL sequence set forth in SEQ ID NO: 118. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence set forth in SEQ ID NO: 127 and a VL sequence set forth in SEQ ID NO: 130. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence set forth in SEQ ID NO: 139 and a VL sequence set forth in SEQ ID NO: 142. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence set forth in SEQ ID NO: 151 and a VL sequence set forth in SEQ ID NO: 154. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence set forth in SEQ ID NO: 175 and a VL sequence set forth in SEQ ID NO: 178. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence set forth in SEQ ID NO: 187 and a VL sequence set forth in SEQ ID NO: 190. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence set forth in SEQ ID NO: 199 and a VL sequence set forth in SEQ ID NO: 202. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence set forth in SEQ ID NO: 211 and a VL sequence set forth in SEQ ID NO: 214. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence set forth in SEQ ID NO: 223 and a VL sequence set forth in SEQ ID NO: 226. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence set forth in SEQ ID NO: 235 and a VL sequence set forth in SEQ ID NO: 238. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence set forth in SEQ ID NO: 256 and a VL sequence set forth in SEQ ID NO: 257.

[0188] In some embodiments, any of SEQ ID NOs: 163, 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 175, 187, 199, 211, 223, 235, and 254 can be combined with any of SEQ ID NOs: 166, 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 178, 190, 202, 214, 226, 238, and 255.

[0189] In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence having at least about 50%, 60%, 70%, 80%, 90%, 95%, or 99% identity to an illustrative VH sequence provided in SEQ ID NOs: 163, 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 175, 187, 199, 211, 223, 235, and 254; and a VL sequence having at leastabout 50%, 60%, 70%, 80%, 90%, 95%, or 99% identity to an illustrative VL sequence provided in SEQ ID NOs: 166, 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 178, 190, 202, 214, 226, 238, and 255. In some embodiments, an anti-fibrin antibody provided herein comprises a VH sequence provided in SEQ ID NOs: 163, 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 175, 187, 199, 211, 223, 235, and 254, with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acid substitutions, and a VL sequence provided in SEQ ID NOs: 166, 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 178, 190, 202, 214, 226, 238, and 255, with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[0190] In some embodiments, an anti-fibrin antibody provided herein comprises one to three CDRs of a VH domain selected from SEQ ID NOs: 163, 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 175, 187, 199, 211, 223, 235, and 254. In some embodiments, an anti-fibrin antibody provided herein comprises two to three CDRs of a VH domain selected from SEQ ID NOs: 163, 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 175, 187, 199, 211, 223, 235, and 254. In some embodiments, an anti-fibrin antibody provided herein comprises three CDRs of a VH domain selected from SEQ ID NOs: 3163, 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 175, 187, 199, 211, 223, 235, and 254. In some embodiments, the CDRs are Exemplary CDRs. In some embodiments, the CDRs are Kabat CDRs. In some embodiments, the CDRs are Chothia CDRs. In some embodiments, the CDRs are AbM CDRs. In some embodiments, the CDRs are Contact CDRs. In some embodiments, the CDRs are IMGT CDRs.

[0191] In some embodiments, the CDRs are CDRs having at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with a CDR-H1, CDR-H2, or CDR-H3 of SEQ ID NOs: 163, 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 175, 187, 199, 211, 223, 235, and 254. In some embodiments, the CDR-H1 is a CDR-H1 of a VH domain selected from SEQ ID NOs: 163, 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 175, 187, 199, 211, 223, 235, and254, with up to 1, 2, 3, 4, or 5 amino acid substitutions. In some embodiments, the CDR-H2 is a CDR-H2 of a VH domain selected from SEQ ID NOs: 163, 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 175, 187, 199, 211, 223, 235, and 254, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the CDR-H3 is a CDR-H3 of a VH domain selected from SEQ ID NOs: 163, 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 175, 187, 199, 211, 223, 235, and 254, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, an anti-fibrin antibody described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[0192] In some embodiments, an anti-fibrin antibody provided herein comprises one to three CDRs of a VL domain of SEQ ID NOs: 166, 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 178, 190, 202, 214, 226, 238, and 255. In some embodiments, an anti-fibrin antibody provided herein comprises two to three CDRs of a VL domain of SEQ ID NOs: 166, 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 178, 190, 202, 214, 226, 238, and 255. In some embodiments, an anti-fibrin antibody provided herein comprises three CDRs of a VL domain of SEQ ID NOs: 166, 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 178, 190, 202, 214, 226, 238, and 255. In some embodiments, the CDRs are Exemplary CDRs. In some embodiments, the CDRs are Kabat CDRs. In some embodiments, the CDRs are Chothia CDRs. In some embodiments, the CDRs are AbM CDRs. In some embodiments, the CDRs are Contact CDRs. In some embodiments, the CDRs are IMGT CDRs.

[0193] In some embodiments, the CDRs are CDRs having at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with a CDR-L1, CDR-L2, or CDR-L3 of SEQ ID NOs: 166, 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 178, 190, 202, 214, 226, 238, and 255. In some embodiments, the CDR-L1 is a CDR-L1 of a VL domain of SEQ ID NOs: 166, 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 178, 190, 202, 214, 226, 238, and 255, with up to 1, 2, 3, 4, or 5 amino acid substitutions. In some embodiments, the CDR-L2 is a CDR- L2 of a VL domain of SEQ ID NOs: 166, 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 178, 190, 202, 214, 226, 238, and 255, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acidsubstitutions. In some embodiments, the CDR-L3 is a CDR-L3 of a VL domain of SEQ ID NOs: 166, 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 178, 190, 202, 214, 226, 238, and 255, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, an anti-fibrin antibody described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[0194] In some embodiments, an anti-fibrin antibody provided herein comprises one to three CDRs of a VH domain selected from SEQ ID NOs: 163, 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 175, 187, 199, 211, 223, 235, and 254 and one to three CDRs of a VL domain of SEQ ID NOs: 166, 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 178, 190, 202, 214, 226, 238, and 255. In some embodiments, an anti-fibrin antibody provided herein comprises two to three CDRs of a VH domain selected from SEQ ID NOs: 163, 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 175, 187, 199, 211, 223, 235, and 254 and two to three CDRs of a VL domain of SEQ ID NOs: 166, 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 178, 190, 202, 214, 226, 238, and 255. In some embodiments, an anti- fibrin antibody provided herein comprises three CDRs of a VH domain selected from SEQ ID NOs: 163, 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 175, 187, 199, 211, 223, 235, and 254 and three CDRs of a VL domain of SEQ ID NOs: 166, 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 178, 190, 202, 214, 226, 238, and 255. In some embodiments, the CDRs are Exemplary CDRs. In some embodiments, the CDRs are Kabat CDRs. In some embodiments, the CDRs are Chothia CDRs. In some embodiments, the CDRs are AbM CDRs. In some embodiments, the CDRs are Contact CDRs. In some embodiments, the CDRs are IMGT CDRs.

[0195] In some embodiments, an anti-fibrin antibody provided herein comprises a CDR- H1 of SEQ ID NO: 1, a CDR-H2 of SEQ ID NO: 2, a CDR-H3 of SEQ ID NO: 3, a CDR-L1 of SEQ ID NO: 4, a CDR-L2 of SEQ ID NO: 5, and a CDR-L3 of SEQ ID NO: 6.

[0196] In some embodiments, an anti-fibrin antibody provided herein comprises a CDR- H1 of SEQ ID NO: 13, a CDR-H2 of SEQ ID NO: 14, a CDR-H3 of SEQ ID NO: 15, aCDR-L1 of SEQ ID NO: 16, a CDR-L2 of SEQ ID NO: 17, and a CDR-L3 of SEQ ID NO: 18.

[0197] In some embodiments, an anti-fibrin antibody provided herein comprises a CDR- H1 of SEQ ID NO: 25, a CDR-H2 of SEQ ID NO: 26, a CDR-H3 of SEQ ID NO: 27, a CDR-L1 of SEQ ID NO: 28, a CDR-L2 of SEQ ID NO: 29, and a CDR-L3 of SEQ ID NO: 30.

[0198] In some embodiments, an anti-fibrin antibody provided herein comprises a CDR- H1 of SEQ ID NO: 37, a CDR-H2 of SEQ ID NO: 38, a CDR-H3 of SEQ ID NO: 39, a CDR-L1 of SEQ ID NO: 40, a CDR-L2 of SEQ ID NO: 41, and a CDR-L3 of SEQ ID NO: 42.

[0199] In some embodiments, an anti-fibrin antibody provided herein comprises a CDR- H1 of SEQ ID NO: 49, a CDR-H2 of SEQ ID NO: 50, a CDR-H3 of SEQ ID NO: 51, a CDR-L1 of SEQ ID NO: 52, a CDR-L2 of SEQ ID NO: 53, and a CDR-L3 of SEQ ID NO: 54.

[0200] In some embodiments, an anti-fibrin antibody provided herein comprises a CDR- H1 of SEQ ID NO: 61, a CDR-H2 of SEQ ID NO: 62, a CDR-H3 of SEQ ID NO: 63, a CDR-L1 of SEQ ID NO: 64, a CDR-L2 of SEQ ID NO: 65, and a CDR-L3 of SEQ ID NO: 66.

[0201] In some embodiments, an anti-fibrin antibody provided herein comprises a CDR- H1 of SEQ ID NO: 73, a CDR-H2 of SEQ ID NO: 74, a CDR-H3 of SEQ ID NO: 75, a CDR-L1 of SEQ ID NO: 76, a CDR-L2 of SEQ ID NO: 77, and a CDR-L3 of SEQ ID NO: 78.

[0202] In some embodiments, an anti-fibrin antibody provided herein comprises a CDR- H1 of SEQ ID NO: 85, a CDR-H2 of SEQ ID NO: 86, a CDR-H3 of SEQ ID NO: 87, a CDR-L1 of SEQ ID NO: 88, a CDR-L2 of SEQ ID NO: 89, and a CDR-L3 of SEQ ID NO: 90.

[0203] In some embodiments, an anti-fibrin antibody provided herein comprises a CDR- H1 of SEQ ID NO: 97, a CDR-H2 of SEQ ID NO: 98, a CDR-H3 of SEQ ID NO: 99, a CDR-L1 of SEQ ID NO: 100, a CDR-L2 of SEQ ID NO: 101, and a CDR-L3 of SEQ ID NO: 102.

[0204] In some embodiments, an anti-fibrin antibody provided herein comprises a CDR- H1 of SEQ ID NO: 109, a CDR-H2 of SEQ ID NO: 110, a CDR-H3 of SEQ ID NO: 111, aCDR-L1 of SEQ ID NO: 112, a CDR-L2 of SEQ ID NO: 113, and a CDR-L3 of SEQ ID NO: 114.

[0205] In some embodiments, an anti-fibrin antibody provided herein comprises a CDR- H1 of SEQ ID NO: 121, a CDR-H2 of SEQ ID NO: 122, a CDR-H3 of SEQ ID NO: 123, a CDR-L1 of SEQ ID NO: 124, a CDR-L2 of SEQ ID NO: 125, and a CDR-L3 of SEQ ID NO: 126.

[0206] In some embodiments, an anti-fibrin antibody provided herein comprises a CDR- H1 of SEQ ID NO: 133, a CDR-H2 of SEQ ID NO: 134, a CDR-H3 of SEQ ID NO: 135, a CDR-L1 of SEQ ID NO: 136, a CDR-L2 of SEQ ID NO: 137, and a CDR-L3 of SEQ ID NO: 138.

[0207] In some embodiments, an anti-fibrin antibody provided herein comprises a CDR- H1 of SEQ ID NO: 145, a CDR-H2 of SEQ ID NO: 146, a CDR-H3 of SEQ ID NO: 147, a CDR-L1 of SEQ ID NO: 148, a CDR-L2 of SEQ ID NO: 149, and a CDR-L3 of SEQ ID NO: 150.

[0208] In some embodiments, an anti-fibrin antibody provided herein comprises a CDR- H1 of SEQ ID NO: 157, a CDR-H2 of SEQ ID NO: 158, a CDR-H3 of SEQ ID NO: 159, a CDR-L1 of SEQ ID NO: 160, a CDR-L2 of SEQ ID NO: 161, and a CDR-L3 of SEQ ID NO: 162.

[0209] In some embodiments, an anti-fibrin antibody provided herein comprises a CDR- H1 of SEQ ID NO: 169, a CDR-H2 of SEQ ID NO: 170, a CDR-H3 of SEQ ID NO: 171, a CDR-L1 of SEQ ID NO: 172, a CDR-L2 of SEQ ID NO: 173, and a CDR-L3 of SEQ ID NO: 174.

[0210] In some embodiments, an anti-fibrin antibody provided herein comprises a CDR- H1 of SEQ ID NO: 181, a CDR-H2 of SEQ ID NO: 182, a CDR-H3 of SEQ ID NO: 183, a CDR-L1 of SEQ ID NO: 184, a CDR-L2 of SEQ ID NO: 185, and a CDR-L3 of SEQ ID NO: 186.

[0211] In some embodiments, an anti-fibrin antibody provided herein comprises a CDR- H1 of SEQ ID NO: 193, a CDR-H2 of SEQ ID NO: 194, a CDR-H3 of SEQ ID NO: 195, a CDR-L1 of SEQ ID NO: 196, a CDR-L2 of SEQ ID NO: 197, and a CDR-L3 of SEQ ID NO: 198.

[0212] In some embodiments, an anti-fibrin antibody provided herein comprises a CDR- H1 of SEQ ID NO: 205, a CDR-H2 of SEQ ID NO: 206, a CDR-H3 of SEQ ID NO: 207, aCDR-L1 of SEQ ID NO: 208, a CDR-L2 of SEQ ID NO: 209, and a CDR-L3 of SEQ ID NO: 210.

[0213] In some embodiments, an anti-fibrin antibody provided herein comprises a CDR- H1 of SEQ ID NO: 217, a CDR-H2 of SEQ ID NO: 218, a CDR-H3 of SEQ ID NO: 219, a CDR-L1 of SEQ ID NO: 220, a CDR-L2 of SEQ ID NO: 221, and a CDR-L3 of SEQ ID NO: 222.

[0214] In some embodiments, an anti-fibrin antibody provided herein comprises a CDR- H1 of SEQ ID NO: 229, a CDR-H2 of SEQ ID NO: 230, a CDR-H3 of SEQ ID NO: 231, a CDR-L1 of SEQ ID NO: 232, a CDR-L2 of SEQ ID NO: 233, and a CDR-L3 of SEQ ID NO: 234.

[0215] In some embodiments, the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, or CDR-L3 selected of SEQ ID NOs: 157, 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 169, 181, 193, 205, 217, 229, and 258; 158, 2, 14, 26, 38, 50, 62, 74, 86, 98, 110, 122, 134, 146, 170, 182, 194, 206, 218, 230 and 259; 159, 3, 15, 27, 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 171, 183, 195, 207, 219, 231, and 260; 160, 4, 16, 28, 40, 52, 64, 76, 88, 100, 112, 124, 136, 148, 172, 184, 196, 208, 220, 232 and 262; 161, 5, 17, 29, 41, 53, 65, 77, 89, 101, 113, 125, 137, 149, 173, 185, 197, 209, 221, 233 and 263; and 162, 6, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 174, 186, 198, 210, 222, 234 and 264, respectively, includes up to 1, 2, 3, 4, or 5 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, an anti-fibrin antibody described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.Epitopes

[0216] In some embodiments, described herein are fibrin antigen binding regions that bind human fibrin yC or the fibrinogen yC domain, wherein the anti-fibrin antibody binds human fibrin at any one of amino acid residues Lys 411, He 412, He 413, Phe 415, Asn 416, Arg 417, Leu 418, Thr 419, He 420, and Gly 421 relative to SEQ ID NO: 265 (human fibrinogen gamma chain isoform gamma-A precursor (NP_000500.2; RefSeq AccessionNM_000509.6)). As used herein, Lys 411, He 412, He 413, Phe 415, Asn 416, Arg 417, Leu 418, Thr 419, He 420, and Gly 421 relative to SEQ ID NO: 265, is also referred to as YSMKKTTMKIIPFNRLTIG (SEQ ID NO: 241), as well as by the terminology of y377-395 (P2) epitope of the fibrin yC or fibrinogen yC domain. In some embodiments, the anti-fibrin antibody binds human fibrin at least two, three, four, five, six, seven, eight, nine, or all ten of amino acid residues Lys 411, He 412, He 413, Phe 415, Asn 416, Arg 417, Leu 418, Thr 419, He 420, and Gly 421 relative to SEQ ID NO: 265 (also known as y377-395 (P2) epitope of the fibrin yC or fibrinogen yC domain). In some embodiments, the anti-fibrin antibody binds human fibrin at amino acid residues Lys 411, He 412, He 413, Phe 415, Asn 416, Arg 417, Leu 418, Thr 419, He 420, and Gly 421 relative to SEQ ID NO: 265 (also known as y377-395 (P2) epitope of the fibrin yC or fibrinogen yC domain). In some embodiments the amino acid residue of the human fibrin yC or fibrinogen yC domain epitope bind the paratope of the antigen binding region with a distance of less than 5 Angstroms or less, 4 Angstroms or less, 3 Angstroms or less, or 2 Angstroms or less. In some embodiments, the isolated antibody binds human fibrin as measured by alanine scanning, X-ray crystallography, a peptide array, hydrogen-deuterium exchange, cryo-electron microscopy, or antibody binding epitope mapping, as known by a skilled artisan, or any suitable method known in the art.Paratopes

[0217] In some embodiments, the fibrin antigen binding regions described herein comprise a VH region (e.g., selected from a sequence set forth in any one of SEQ ID NOs: 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 163, 175, 187, 199, 211, 223, or 235) comprising a paratope that binds human fibrin yC or fibrinogen yC domain, wherein the paratope comprises any one of amino acid residues Ser 31, Tyr 32, Trp 33, His 35, Trp 47, Leu 50, Asp 52, Asp 54, Tyr 56, Ala 93, Ser 94, Ser 95, Lys 96 or Asp 96, Pro 97 or Ala 97, Gly 101, Gly 102, and Trp 103. In some embodiments, the anti-fibrin antibody comprises a VH region (e.g., selected from a sequence set forth in any one of SEQ ID NOs: 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 163, 175, 187, 199, 211, 223, or 235) comprising a paratope that comprises at least two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, or all seventeen of amino acid residues Ser 31, Tyr 32, Trp 33, His 35, Trp 47, Leu 50, Asp 52, Asp 54, Tyr 56, Ala 93, Ser 94, Ser 95, Lys 96 or Asp 96, Pro 97 or Ala 97, Gly 101, Gly 102, and Trp 103. In some embodiments, the antigen binding regions comprises a VH region (e.g., selected from a sequence set forth in any one ofSEQ ID NOs: 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 163, 175, 187, 199, 211, 223, or 235) comprising a paratope that comprises amino acid residues Ser 31, Trp 33, His 35, Asp 52, Asp 54, Tyr 56, Ser 94, Gly 101, Gly 102, and Trp 103. In some embodiments, the anti-fibrin antibody comprises a VH region (e.g., selected from a sequence set forth in any one of SEQ ID NOs: 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 163, 175, 187, 199, 211, 223, or 235) comprising a paratope that comprises amino acid residues Ser 31, Trp 33, His 35, Asp 52, Asp 54, Tyr 56, Ala 93, Ser 94, Lys 96, Pro 97, Gly 101, Gly 102, and Trp 103. In some embodiments, the anti-fibrin antibody comprises a VH region (e.g., selected from a sequence set forth in any one of SEQ ID NOs: 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 163, 175, 187, 199, 211, 223, or 235) comprising a paratope that comprises amino acid residues Ser 31, Tyr 32, Trp 33, His 35, Trp 47, Asp 52, Asp 54, Tyr 56, Ser 94, Ser 95, Asp 96, Ala 97, Gly 101, Gly 102, and Trp 103.

[0218] In some embodiments, the anti-fibrin antibody comprises a VL region (e.g., selected from a sequence set forth in SEQ ID NOs: 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 166, 178, 190, 202, 214, 226, or 238) comprising a paratope that comprises any one of amino acid residues His 27, Tyr 32, Tyr 36, Leu 46, Tyr 49, Gin 50, Ala 91 or Asn 91, Leu 92, Leu 94, and Leu 96. In some embodiments, the antigen binding regions comprises a VL region (e.g., selected from a sequence set forth in SEQ ID NOs: 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 166, 178, 190, 202, 214, 226, or 238) comprising a paratope that comprises at least two, three, four, five, six, seven, eight, nine or all ten amino acid residues His 27, Tyr 32, Tyr 36, Leu 46, Tyr 49, Gin 50, Ala 91 or Asn 91, Leu 92, Leu 94, and Leu 96. In some embodiments, the antigen binding regions comprises a VL region (e.g., selected from a sequence set forth in SEQ ID NOs: 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 166, 178, 190, 202, 214, 226, or 238) comprising a paratope that comprises the amino acid residues His 27, Tyr 32, Tyr 36, Leu 46, Gin 50, Leu 92, Leu 94, and Leu 96. In some embodiments, the antigen binding regions comprises a VL region (e.g, selected from a sequence set forth in SEQ ID NOs: 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 166, 178, 190, 202, 214, 226, or 238) comprising a paratope that comprises the amino acid residues His 27, Tyr 32, Tyr 36, Leu 46, Gin 50, Asn 91, Leu 92, Leu 94, and Leu 96. In some embodiments, the antigen binding regions comprises a VL region (e.g, selected from a sequence set forth in SEQ ID NOs: 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 166, 178, 190, 202, 214, 226, or 238) comprising a paratope that comprises the aminoacid residues His 27, Tyr 32, Tyr 36, Leu 46, Tyr 49, Gin 50, Ala 91, Leu 92, Leu 94, and Leu 96.

[0219] In some embodiments the paratope of the anti-fibrin antibody binds the amino acid residues of the human fibrin yC or fibrinogen yC domain epitope with a distance of less than 5 Angstroms or less, 4 Angstroms or less, 3 Angstroms or less, or 2 Angstroms or less.Fc Region

[0220] In some embodiments, anti-fibrin antibodies described herein comprise a human Fc domain. In some embodiments, the human Fc domain of anti-fibrin antibodies described herein comprises two or more amino acid substitutions relative to the sequence set forth in SEQ ID NO: 164. In some embodiments, the two or more substitutions comprise amino acid substitutions L234A and L235A (LALA) relative to the sequence set forth in SEQ ID NO: 164. In some embodiments, such an exemplary anti-fibrin antibody comprises the heavy and light chain of SEQ ID NOs: 244 and 245, respectively. In some embodiments, the two or more substitutions, including at least L234A and L235A, result in result in increased half-life, reduced FcyR binding, reduced Clq binding, reduced or increased FcRn binding, reduced or increased ADCC activity, reduced or increased ADCP activity, or reduced or increased CDC activity compared with the Fc without the two or more substitutions.

[0221] Without being bound by theory, L234A and L235A modifications minimize antibody binding to FcyRs and Clq and eliminate antibody effector functions. Since the anti- fibrin antibodies described herein bind specifically to fibrin clots and not to cells, the risks of effector cell-mediated toxicity are low. The LALA (Fc null) mutation minimizes the potential risk of effector cell-mediated toxicity even further. For example, in some embodiments, the LALA mutation in anti-fibrin antibodies described herein, such as ADI-60143 LALA, reduces the risk of MRI abnormalities resembling amyloid related imaging abnormalities (ARIA) via FcyR and Clq binding. For example, some of the known risks of anti-Ap treatments, particularly cerebral edema and microhemorrhage (known as ARIA), limit use of mAbs currently indicated for the treatment of various neurodegenerative diseases. Without being bound by theory, anti-Ap ARIA risk may be caused or exasperated by 1) FcyR microglia and macrophage recruitment and activation and 2) Clq activation of the classical complement pathway. Exemplary anti-fibrin antibodies of the disclosure, such as ADI-60143 LALA (which harbors L234A and L235A (LALA) modifications to reduce both FcyR and Clq binding) has a reduced additive risk of MRI imaging abnormalities resembling ARIA.Such amelioration of risk of ARIA-like pathology by the anti-fibrin antibodies described herein also enables the capability of said anti-fibrin antibodies to treat AP0E4 homozygotes that are susceptible to ARAL Therefore, anti-fibrin antibodies described herein, without being bound by theory, in some embodiments, reduce the risk for ‘amyloid related imaging abnormalities-like’ or ‘ARIA-like’ pathology, and, accordingly, in some embodiments, anti- fibrin antibodies described herein can be provided at higher doses than canonical mAbs currently indicated for the treatment of various neurodegenerative diseases.

[0222] The structures of the Fc regions of various immunoglobulins, and the glycosylation sites contained therein, are known in the art. See Schroeder and Cavacini, J. Allergy Clin. Immunol., 2010, 125:S41-52, incorporated by reference in its entirety. The Fc region may be a naturally occurring Fc region, or an Fc region modified as described in the art or elsewhere in this disclosure.

[0223] Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991. An “Fc polypeptide” of a dimeric Fc as used herein refers to one of the two polypeptides forming the dimeric Fc domain, i.e. a polypeptide comprising C-terminal constant regions of an immunoglobulin heavy chain, capable of stable self-association. For example, an Fc polypeptide of a dimeric IgG Fc comprises an IgG CH2 and an IgG CH3 constant domain sequence. An Fc can be of the class IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGi, IgG?, IgG?, IgG4, IgAi, and IgA?; or IgGl, IgG2, IgG3, and IgG4.

[0224] The terms “Fc receptor” and “FcR” are used to describe a receptor that binds to the Fc region of an anti-fibrin antibody or an antibody. For example, an FcR is a native sequence human FcR. Generally, an FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and FcyRIII subclasses, including allelic variants and alternatively spliced forms of these receptors. FcyRII receptors include FcyRIIA (an “activating receptor”) and FcyRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. Immunoglobulins of other isotypes can also be bound by certain FcRs (see, e.g., aneway et al., Immuno Biology: the immune system in health and disease, (Elsevier Science Ltd., NY) (4th ed., 1999)). Activating receptor FcyRIIA contains an immunoreceptor tyrosine-basedactivation motif (IT AM) in its cytoplasmic domain. Inhibiting receptor FcyRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain (reviewed in Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term “FcR” herein. The term also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976); and Kim et al., J. Immunol. 24:249 (1994)).

[0225] Modifications in the CH2 domain can affect the binding of FcRs to the Fc. A number of amino acid modifications in the Fc region are known in the art for selectively altering the affinity of the Fc for different Fc gamma receptors. In some embodiments, the Fc comprises one or more modifications to promote selective binding of Fc-gamma receptors.

[0226] Exemplary mutations that alter the binding of FcRs to the Fc are listed below: S298A / E333A / K334A, S298A / E333A / K334A / K326A (Lu Y, Vernes JM, Chiang N, et al. J Immunol Methods. 2011 Feb 28;365(l-2): 132-41);F243L / R292P / Y300L / V305I / P396L, F243L / R292P / Y300L / L235V / P396L (Stavenhagen JB, Gorlatov S, Tuaillon N, et al. Cancer Res. 2007 Sep 15;67(18):8882-90; Nordstrom JL, Gorlatov S, Zhang W, et al. Breast Cancer Res. 2011 Nov 30;13(6):R123); F243L (Stewart R, Thom G, Levens M, et al. Protein Eng Des Sei. 2011 Sep;24(9):671-8.), S298A / E333A / K334A (Shields RL, Namenuk AK, Hong K, et al. J Biol Chem. 2001 Mar 2;276(9):6591-604); S239D / I332E / A330L, S239D / I332E (Lazar GA, Dang W, Karki S, et al. Proc Natl Acad Sci U S A. 2006 Mar 14; 103(11):4005-10); S239D / S267E, S267E / L328F (Chu SY, Vostiar I, Karki S, et al. Mol Immunol. 2008 Sep;45(15):3926-33);S239D / D265S / S298A / I332E, S239E / S298A / K326A / A327H, G237F / S298A / A330L / I332E, S 239D / I332E / S298A, S239D / K326E / A330L / I332E / S298A, G236A / S239D / D270L / I332E, S2 39E / S267E / H268D, L234F / S267E / N325L, G237F / V266L / S267D and other mutations listed in WO2011 / 120134 and WO2011 / 120135, herein incorporated by reference. Therapeutic Antibody Engineering (by William R. Strohl and Lila M. Strohl, Woodhead Publishing series in Biomedicine No 11, ISBN 1 907568 37 9, Oct 2012) lists mutations on page 283.

[0227] In some embodiments an antibody described herein includes modifications to improve its ability to mediate effector function. Such modifications are known in the art and include afucosylation, or engineering of the affinity of the Fc towards an activating receptor,mainly FCGR3a for ADCC, and towards Clq for CDC. The following Table 2 summarizes various designs reported in the literature for effector function engineering.

[0228] Methods of producing antigen-binding proteins with little or no fucose on the Fc glycosylation site (Asn 297 EU numbering) without altering the amino acid sequence are well known in the art. The GlymaX® technology (ProBioGen AG) is based on the introduction of a gene for an enzyme which deflects the cellular pathway of fucose biosynthesis into cells used for antigen-binding protein production. This prevents the addition of the sugar “fucose” to the N-linked antigen-binding protein carbohydrate part by antigen-binding proteinproducing cells (von Horsten et al. (2010) Glycobiology . 2010 Dec; 20 (12): 1607-18).Another approach to obtaining antigen-binding proteins with lowered levels of fucosylation can be found in U.S. Patent No. 8,409,572, which teaches selecting cell lines for antibody production for their ability to yield lower levels of fucosylation on antibodies can be fully afucosylated (meaning they contain no detectable fucose) or they can be partially afucosylated, meaning that the isolated antigen-binding protein contains less than 95%, less than 85%, less than 75%, less than 65%, less than 55%, less than 45%, less than 35%, less than 25%, less than 15%, or less than 5% of the amount of fucose normally detected for a similar antigen-binding protein produced by a mammalian expression system.

[0229] Thus, in some embodiments, an antibody described herein can include a dimeric Fc that comprises one or more amino acid modifications as noted in Table 2 that confer improved effector function. In some embodiments, the antibody can be afucosylated to improve effector function.Table 2: CH2 Domains and Effector Function Engineering

[0230] Fc modifications reducing FcgR and / or complement binding and / or effector function are known in the art. Recent publications describe strategies that have been used to engineer antibodies with reduced or silenced effector activity (see Strohl, WR (2009), Curr Opin Biotech 20:685-691, and Strohl, WR and Strohl LM, “Antibody Fc engineering for optimal antibody performance” In Therapeutic Antibody Engineering, Cambridge: Woodhead Publishing (2012), pp 225-249). These strategies include reduction of effector function through modification of glycosylation, use of IgG2 / IgG4 scaffolds, or the introduction of mutations in the hinge or CH2 regions of the Fc. For example, US Patent Publication No. 2011 / 0212087 (Strohl), International Patent Publication No. WO 2006 / 105338 (Xencor), US Patent Publication No. 2012 / 0225058 (Xencor), US Patent Publication No. 2012 / 0251531 (Genentech), and Strop et al ((2012) J. Mol. Biol. 420: 204- 219) describe specific modifications to reduce FcgR or complement binding to the Fc.

[0231] Specific, non-limiting examples of known amino acid modifications to reduce FcgR or complement binding to the Fc include those identified in the following Table 3:Table 3: Modifications to Reduce FcyR or Complement Binding to the Fc

[0232] Methods of producing antibodies with little or no fucose on the Fc glycosylation site (Asn 297 EU numbering) without altering the amino acid sequence are well known in the art. The GlymaxX® technology (ProBioGen AG) is based on the introduction of a gene for an enzyme which deflects the cellular pathway of fucose biosynthesis into cells used for antibody production. This prevents the addition of the sugar “fucose” to the N-linked antibody carbohydrate part by antibody-producing cells, (von Horsten et al. (2010) Glycobiology. 2010 Dec; 20 (12): 1607-18.) Examples of cell lines capable of producing defucosylated antibodies include CHO-DG44 with stable overexpression of the bacterial oxidoreductase GDP-6-deoxy-D-lyxo-4-hexylose reductase (RMD) (see Henning von Horsten et al., Glycobiol 2010, 20: 1607-1618) or Lecl3 CHO cells, which are deficient in protein fucosylation (see Ripka et al., Arch. Biochem. Biophys., 1986, 249:533-545; U.S. Pat. Pub. No. 2003 / 0157108; WO 2004 / 056312; each of which is incorporated by reference in its entirety), and knockout cell lines, such as alpha- 1,6-fucosyltransferase gene or FUT8 knockout CHO cells (see Yamane-Ohnuki et al., Biotech. Bioeng., 2004, 87: 614-622; Kanda et al., Biotechnol. Bioeng., 2006, 94:680-688; and WO 2003 / 085107; each of which is incorporated by reference in its entirety). Another approach to obtaining antibodies with lowered levels of fucosylation can be found in U.S. Patent No. 8,409,572, which teaches selecting cell lines for antibody production for their ability to yield lower levels of fucosylation on antibodies.

[0233] Examples of cell lines capable of producing defucosylated antibody include CHO- DG44 with stable overexpression of the bacterial oxidoreductase GDP-6-deoxy-D-lyxo-4- hexylose reductase (RMD) (see Henning von Horsten et al., Glycobiol 2010, 20: 1607-1618) or Lecl3 CHO cells, which are deficient in protein fucosylation (see Ripka et al., Arch. Biochem. Biophys., 1986, 249:533-545; U.S. Pat. Pub. No. 2003 / 0157108; WO 2004 / 056312; each of which is incorporated by reference in its entirety), and knockout cell lines, such as alpha- 1,6-fucosyltransferase gene or FUT8 knockout CHO cells (see Yamane-Ohnuki et al.,Biotech. Bioeng., 2004, 87: 614-622; Kanda et al., BiotechnoL Bioeng., 2006, 94:680-688; and WO 2003 / 085107; each of which is incorporated by reference in its entirety).

[0234] Antibodies can be fully afucosylated (meaning they contain no detectable fucose) or they can be partially afucosylated, meaning that the isolated antibody contains less than 95%, less than 85%, less than 75%, less than 65%, less than 55%, less than 45%, less than 35%, less than 25%, less than 15%, or less than 5% of the amount of fucose normally detected for a similar antibody produced by a mammalian expression system.

[0235] In some embodiments, an antibody provided herein comprises an IgGl domain with reduced fucose content at position Asn 297 compared to a naturally occurring IgGl domain. Such Fc domains are known to have improved ADCC. See Shields et al., J. Biol. Chem., 2002, 277:26733-26740, incorporated by reference in its entirety. In some embodiments, such antibodies do not comprise any fucose at position Asn 297. The amount of fucose may be determined using any suitable method, for example as described in WO 2008 / 077546, incorporated by reference in its entirety.

[0236] In some embodiments, an antibody provided herein comprises an Fc region with one or more amino acid substitutions which improve ADCC, such as a substitution at one or more of positions 298, 333, and 334 of the Fc region. In some embodiments, an antibody provided herein comprises an Fc region with one or more amino acid substitutions at positions 239, 332, and 330, as described in Lazar et al., Proc. Natl. Acad. Sci. USA, 2006,103:4005-4010, incorporated by reference in its entirety.

[0237] Other illustrative glycosylation variants which may be incorporated into the antibodies provided herein are described, for example, in U.S. Pat. Pub. Nos. 2003 / 0157108, 2004 / 0093621, 2003 / 0157108, 2003 / 0115614, 2002 / 0164328, 2004 / 0093621, 2004 / 0132140, 2004 / 0110704, 2004 / 0110282, 2004 / 0109865; International Pat. Pub. Nos. 2000 / 61739, 2001 / 29246, 2003 / 085119, 2003 / 084570, 2005 / 035586, 2005 / 035778; 2005 / 053742, 2002 / 031140; Okazaki et al., J. Mol. BioL, 2004, 336: 1239-1249; and Yamane-Ohnuki et al., Biotech. Bioeng., 2004, 87: 614-622; each of which is incorporated by reference in its entirety.

[0238] In some embodiments, an antibody provided herein comprises an Fc region with at least one galactose residue in the oligosaccharide attached to the Fc region. Such antibody variants may have improved CDC function. Examples of such antibody variants are described, for example, in WO 1997 / 30087; WO 1998 / 58964; and WO 1999 / 22764; each of which his incorporated by reference in its entirety.

[0239] In some embodiments, an antibody provided herein comprises one or more alterations that improves or diminishes Clq binding and / or CDC. See U.S. Pat. No.6,194,551; WO 99 / 51642; and Idusogie et al., J. Immunol., 2000, 164:4178-4184; each of which is incorporated by reference in its entirety.

[0240] In certain embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions result in a decrease in one or more of ADCC activity, ADCP activity, or CDC activity compared with the Fc without the one or more substitutions.

[0241] In certain embodiments, the one or more amino acid substitutions is selected from the group consisting of S228P (SP), M252Y, S254T, T256E, M260Y, S262T, T264E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, P329A (PA), P329G (PG), P331S (PS), Q411H, Q311V, A378V, E380A, M428L, N434A, N434S, N297A, D265A, L234A, L235A, L242A, L243A, and N434W (direct numbering system). In certain embodiments, the one or more amino acid substitutions comprises a specific combination of amino acid substitutions selected from the group consisting of M428L / N434S (LS);M252Y / S254T / T256E (YTE); T250Q / M428L; T307A / E380A / N434A; T256D / T307Q (DQ); T256D / T307W (DW); M252Y / T256D (YD); T307Q / Q311V / A378V (QVV);T256D / H285D / T307R / Q311V / A378V (DDRVV); L309D / Q311H / N434S (DHS); S228P / L235E (SPLE); L234A / L235A (LALA); LALA / PA; LALA / PS; LALA / PG; LALA / LS; LALA / YTE; M428L / N434A; L234A / G237A (LAGA); L234A / L235A / G237A (LALAGA); L234A / L235A / P329G; D265A / YTE; LALA / YTE; LAGA / YTE;LALAGA / YTE; LALAPG / YTE; N297A / LS; D265A / LS; LALAGA / LS; LALAPG / LS; N297A / DHS; D265A / DHS; LALA / DHS; LAGA / DHS; LALAGA / DHS; LALAPG / DHS; SP / YTE; SPLE / YTE; SP / LS; SPLE / LS; SP / DHS; SPLE / DHS; N297A / LA; D265A / LA; LALA / LA; LAGA / LA; LALAGA / LA; LALAPG / LA; N297A / N434A; D265A / N434A; LALA / N434A; LAGA / N434A; LALAGA / N434A; LALAPG / N434A; N297A / N434W; D265A / N434W; LALA / N434W; LAGA / N434W; LALAGA / N434W; LALAPG / N434W; N297A / DQ; D265A / DQ; LALA / DQ; LAGA / DQ; LALAGA / DQ; LALAPG / DQ;N297A / DW; D265A / DW; LALA / DW; LAG A / D W; LALAGA / DW; LALAPG / DW N297A / YD; D265A / YD; LALA / YD; LAGA / YD; LALAGA / YD; LALAPG / YD;T307Q / Q311V / A378V (QVV); N297A / QVV; D265A / QVV; LALA / QVV; LAGA / QVV; LALAGA / QVV; LALAPG / QVV; DDRVV; N297A / DDRVV; D265A / DDRVV;LALA / DDRVV; LAGA / DDRVV; LALAGA / DDRVV; and LALAPG / DDRVV.

[0242] In certain embodiments the human Fc region comprises a human IgGl Fc with LALA mutations. For example, a human Fc region can comprise a human IgGl Fc with LALA mutations at L42A / L243 A (EU numbering system). In certain embodiments the human Fc region comprises a human IgGl Fc with LALA / YTE mutations. In certain embodiments the human Fc region comprises a human IgGl Fc with LALA / LS mutations. In certain embodiments the human Fc region comprises a human IgGl Fc with LALA / PA mutations. In certain embodiments the human Fc region comprises a human IgGl Fc with LALA / PG mutations. In certain embodiments the human Fc region comprises a human IgGl Fc with LALA / PS mutations.Doses

[0243] Described herein, in some embodiments, are dosage forms comprising anti-fibrin antibodies described herein, wherein the anti-fibrin antibody in the dosage form is at a concentration of from about 20 mg / mL to about 200 mg / mL (e.g., from about 40 mg / mL to about 180 mg / mL, 50 mg / mL to about 150 mg / mL, 70 mg / mL to about 120 mg / mL, and 90 mg / mL to about 110 mg / mL). In some embodiments, the dosage form is at a concentration of greater than about 40, 60, 80, 100, 120, 160, 180, or 200 mg / mL, or at a concentration of about 120 mg / mL. In some embodiments, the dosage form is at a concentration of about 100 mg / mL. In some embodiments, the dosage form is formulated for local (e.g., intravitreal, subconjunctival, retrobulbar, and intracameral) intravenous, intraarterial, subcutaneous, intramuscular, intrathecal, intraperitoneal, topical, intracavitary, or perfusion through a catheter administration. In some embodiments, the dosage form is formulated for intravitreal administration.

[0244] In some embodiments, the dosage form is administered in a volume of from 0.02 mL to 0.2 mL (e.g., from 0.03 mL to 0.15 mL, 0.04 mL to 0.13 mL, or 0.05 mL to 0.1 mL). In some embodiments, the dosage form is administered in a volume of from 0.03 mL to 0.15 mL. In some embodiments, the dosage form is administered in a volume of from 0.04 mL to 0.13 mL. In some embodiments, the dosage form is administered in a volume of from 0.05 mL to 0.1 mL.

[0245] In some embodiments, the dosage form is administered in a volume of about 0.02 mL. In some embodiments, the dosage form is administered in a volume of about 0.03 mL. In some embodiments, the dosage form is administered in a volume of about 0.04 mL. In some embodiments, the dosage form is administered in a volume of about 0.05 mL. In some embodiments, the dosage form is administered in a volume of about 0.06 mL. In someembodiments, the dosage form is administered in a volume of about 0.07 mL. In some embodiments, the dosage form is administered in a volume of about 0.08 mL. In some embodiments, the dosage form is administered in a volume of about 0.09 mL. In some embodiments, the dosage form is administered in a volume of about 0.1 mL. In some embodiments, the dosage form is administered in a volume of about 0.11 mL. In some embodiments, the dosage form is administered in a volume of about 0.12 mL. In some embodiments, the dosage form is administered in a volume of about 0.13 mL. In some embodiments, the dosage form is administered in a volume of about 0.14 mL. In some embodiments, the dosage form is administered in a volume of about 0.15 mL.

[0246] Also described herein, in some embodiments, are methods of treating a disorder or condition of the eye (e.g., retinitis pigmentosa, age-related macular degeneration, glaucoma, diabetic retinopathy (e.g., diabetic macular edema), uveitis, and retinal detachment) in a subject in need thereof, the method comprising administering (e.g., intravitreally administering) to the subject a dosage form comprising an anti-fibrin antibody described herein, wherein the dosage form comprises the anti-fibrin antibody at a concentration of from about 20 mg / mL to about 200 mg / mL (e.g., from about 40 mg / mL to about 180 mg / mL, 50 mg / mL to about 150 mg / mL, 70 mg / mL to about 120 mg / mL, and 90 mg / mL to about 110 mg / mL). In some embodiments, the dosage form is at a concentration of greater than about 40, 60, 80, 100, 120, 160, 180, or 200 mg / mL, or at a concentration of about 120 mg / mL. In some embodiments, the dosage form is at a concentration of about 100 mg / mL.

[0247] Also described herein, in some embodiments, are methods of treating a disorder or condition of the eye (e.g, retinitis pigmentosa, age-related macular degeneration, glaucoma, diabetic retinopathy (e.g, diabetic macular edema), uveitis, and retinal detachment) in a subject in need thereof, the method comprising administering (e.g., intravitreally administering) dosage forms comprising anti-fibrin antibodies described herein to the subject, wherein the subject is administered one or more doses of the dosage form to each eye, wherein each dose comprises about 1 mg to about 20 mg (e.g., about 1.2 mg, about 2.5 mg, about 3.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12 mg, and about 15 mg) to each eye of the isolated antibody. The anti-fibrin antibody can be selected from an anti-fibrin antibody disclosed herein. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 157, a CDR-H2 of SEQ ID NO: 158, and a CDR-H3 of SEQ ID NO: 159, and a VL comprising a CDR-L1 of SEQ ID NO: 160, a CDR-L2 of SEQ ID NO: 161, and a CDR-L3 of SEQ ID NO: 162. In some embodiments, the anti-fibrinantibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 1, a CDR-H2 of SEQ ID NO: 2, and a CDR-H3 of SEQ ID NO: 24, and a VL comprising a CDR-L1 of SEQ ID NO: 4, a CDR-L2 of SEQ ID NO: 5, and a CDR-L3 of SEQ ID NO: 6. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 13, a CDR-H2 of SEQ ID NO: 14, and a CDR-H3 of SEQ ID NO: 15, and a VL comprising a CDR-L1 of SEQ ID NO: 16, a CDR-L2 of SEQ ID NO: 17, and a CDR-L3 of SEQ ID NO: 18. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 25, a CDR-H2 of SEQ ID NO: 26, and a CDR-H3 of SEQ ID NO: 27, and a VL comprising a CDR-L1 of SEQ ID NO: 28, a CDR-L2 of SEQ ID NO: 29, and a CDR-L3 of SEQ ID NO: 30. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 37, a CDR-H2 of SEQ ID NO: 38, and a CDR-H3 of SEQ ID NO: 39, and a VL comprising a CDR-L1 of SEQ ID NO: 40, a CDR-L2 of SEQ ID NO: 41, and a CDR-L3 of SEQ ID NO: 42. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 49, a CDR-H2 of SEQ ID NO: 50, and a CDR-H3 of SEQ ID NO: 51, and a VL comprising a CDR-L1 of SEQ ID NO: 52, a CDR-L2 of SEQ ID NO: 53, and a CDR-L3 of SEQ ID NO: 54. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 61, a CDR-H2 of SEQ ID NO: 62, and a CDR-H3 of SEQ ID NO: 63, and a VL comprising a CDR-L1 of SEQ ID NO: 64, a CDR-L2 of SEQ ID NO: 65, and a CDR-L3 of SEQ ID NO: 66. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 73, a CDR-H2 of SEQ ID NO: 74, and a CDR-H3 of SEQ ID NO: 75, and a VL comprising a CDR-L1 of SEQ ID NO: 76, a CDR-L2 of SEQ ID NO: 77, and a CDR-L3 of SEQ ID NO: 78. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 85, a CDR-H2 of SEQ ID NO: 86, and a CDR-H3 of SEQ ID NO: 87, and a VL comprising a CDR-L1 of SEQ ID NO: 88, a CDR-L2 of SEQ ID NO: 89, and a CDR-L3 of SEQ ID NO: 90. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 97, a CDR-H2 of SEQ ID NO: 98, and a CDR-H3 of SEQ ID NO: 99, and a VL comprising a CDR-L1 of SEQ ID NO: 100, a CDR-L2 of SEQ ID NO: 101, and a CDR-L3 of SEQ ID NO: 102. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 109, a CDR-H2 of SEQ ID NO: 110, and a CDR- H3 of SEQ ID NO: 111, and a VL comprising a CDR-L1 of SEQ ID NO: 112, a CDR-L2 of SEQ ID NO: 113, and a CDR-L3 of SEQ ID NO: 114. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 121, a CDR-H2 of SEQ IDNO: 122, and a CDR-H3 of SEQ ID NO: 123, and a VL comprising a CDR-L1 of SEQ ID NO: 124, a CDR-L2 of SEQ ID NO: 125, and a CDR-L3 of SEQ ID NO: 126. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 133, a CDR-H2 of SEQ ID NO: 134, and a CDR-H3 of SEQ ID NO: 135, and a VL comprising a CDR-L1 of SEQ ID NO: 136, a CDR-L2 of SEQ ID NO: 137, and a CDR-L3 of SEQ ID NO: 138. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 145, a CDR-H2 of SEQ ID NO: 146, and a CDR-H3 of SEQ ID NO: 147, and a VL comprising a CDR-L1 of SEQ ID NO: 148, a CDR-L2 of SEQ ID NO: 149, and a CDR-L3 of SEQ ID NO: 150. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 169, a CDR-H2 of SEQ ID NO: 170, and a CDR-H3 of SEQ ID NO: 171, and a VL comprising a CDR-L1 of SEQ ID NO: 172, a CDR-L2 of SEQ ID NO: 173, and a CDR-L3 of SEQ ID NO: 174. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 181, a CDR-H2 of SEQ ID NO: 182, and a CDR-H3 of SEQ ID NO: 183, and a VL comprising a CDR-L1 of SEQ ID NO: 184, a CDR-L2 of SEQ ID NO: 185, and a CDR-L3 of SEQ ID NO: 186. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 193, a CDR-H2 of SEQ ID NO: 194, and a CDR-H3 of SEQ ID NO: 195, and a VL comprising a CDR-L1 of SEQ ID NO: 196, a CDR-L2 of SEQ ID NO: 197, and a CDR-L3 of SEQ ID NO: 198. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 205, a CDR-H2 of SEQ ID NO: 206, and a CDR-H3 of SEQ ID NO: 207, and a VL comprising a CDR-L1 of SEQ ID NO: 208, a CDR-L2 of SEQ ID NO: 209, and a CDR-L3 of SEQ ID NO: 210. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 217, a CDR-H2 of SEQ ID NO: 218, and a CDR-H3 of SEQ ID NO: 219, and a VL comprising a CDR-L1 of SEQ ID NO: 220, a CDR-L2 of SEQ ID NO: 221, and a CDR-L3 of SEQ ID NO: 222. In some embodiments, the anti-fibrin antibody comprises a VH comprising a CDR-H1 of SEQ ID NO: 229, a CDR-H2 of SEQ ID NO: 230, and a CDR-H3 of SEQ ID NO: 231, and a VL comprising a CDR-L1 of SEQ ID NO: 232, a CDR-L2 of SEQ ID NO: 233, and a CDR-L3 of SEQ ID NO: 234.

[0248] In some embodiments, the dosage form comprises anti-fibrin antibodies at a concentration of from about 20 mg / mL to about 200 mg / mL (e.g., from about 40 mg / mL to about 180 mg / mL, 50 mg / mL to about 150 mg / mL, 70 mg / mL to about 120 mg / mL, and 90 mg / mL to about 110 mg / mL). In some embodiments, the dosage form is at a concentration of greater than about 40, 60, 80, 100, 120, 160, 180, or 200 mg / mL, or at a concentration ofabout 120 mg / mL. In some embodiments, the dosage form is at a concentration of about 100 mg / mL of the anti-fibrin antibody.

[0249] In some embodiments, the anti-fibrin antibody is administered at a dose of about 1 mg to about 100 mg to each eye. In some embodiments, the anti-fibrin antibody is administered at a dose of about 1 mg to about 20 mg to each eye. In some embodiments, the anti-fibrin antibody is administered at a dose of about 2.5 mg to about 7.5 mg to each eye. In some embodiments, the anti-fibrin antibody is administered at a dose of about 5 mg to each eye.

[0250] In some embodiments, the anti-fibrin antibody is administered at a dose of about 1 mg, about 1.2 mg, about 2 mg, about 2.5 mg, about 3.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12 mg, about 15 mg, or about 20 mg to each eye. In some embodiments, the anti-fibrin antibody is administered at a dose of about 1 mg to each eye. In some embodiments, the anti-fibrin antibody is administered at a dose of about 1.2 mg to each eye. In some embodiments, the anti-fibrin antibody is administered at a dose of about 2.5 mg to each eye. In some embodiments, the anti-fibrin antibody is administered at a dose of about 3.5 mg to each eye. In some embodiments, the anti-fibrin antibody is administered at a dose of about 5 mg to each eye. In some embodiments, the anti-fibrin antibody is administered at a dose of about 7.5 mg to each eye. In some embodiments, the anti-fibrin antibody is administered at a dose of about 10 mg to each eye. In some embodiments, the anti-fibrin antibody is administered at a dose of about 10 mg or more to each eye. In some embodiments, the anti-fibrin antibody is administered at a dose of about 12 mg to each eye. In some embodiments, the anti-fibrin antibody is administered at a dose of about 15 mg to each eye.

[0251] In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject one, two, three, or four times per month; or once every six or eight weeks for one or more months. In some embodiments, the dosage form comprising the anti- fibrin antibody is administered to a subject about one time per month (e.g., about every four weeks; Q4W) for one, two, three, four, five, six, twelve, twenty-four, forty-eight or more months. In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about two times per month (e.g., about every two weeks; Q2W) for one, two, three, four, five, six, twelve, twenty-four, forty-eight or more months. In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about three times per month for one, two, three, four, five, six, twelve, twenty-four,forty-eight or more months. In some embodiments, the dosage form comprising the antifibrin antibody is administered to a subject about four times per month (e.g., about every week; Q1W) for one, two, three, four, five, six, twelve, twenty-four, forty-eight or more months. In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about once every six weeks (Q6W) for one, two, three, four, five, six, twelve, twenty-four, forty-eight or more months. In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about once every eight weeks (Q8W) for one, two, three, four, five, six, twelve, twenty-four, forty-eight or more months.

[0252] In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about four times per month (e.g., about every week; Q1W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 1 week (Q1W).

[0253] In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about two times per month (e.g., about every two weeks (Q2W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 2 weeks (Q2W).

[0254] In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 3 weeks (Q3W).

[0255] In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about one time per month (e., about every four weeks; Q4W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 4 weeks (Q4W).

[0256] In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 5 weeks (Q5W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 6 weeks (Q6W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 7 weeks (Q7W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 8 weeks (Q8W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 9 weeks (Q9W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 10 weeks (Q10W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 11 weeks (QI 1W). In some embodiments, the dosageform comprising the anti-fibrin antibody is administered to a subject about every 12 weeks (Q12W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 13 weeks (Q13W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 14 weeks (Q14W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 15 weeks (Q15W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 16 weeks (Q16W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 17 weeks (Q17W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 18 weeks (Q18W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 19 weeks (Q19W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 20 weeks (Q20W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 21 weeks (Q21W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 22 weeks (Q22W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 23 weeks (Q23W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 24 weeks (Q24W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 25 weeks (Q25W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 26 weeks (Q26W).

[0257] In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every 2 to 12 weeks (Q2W to Q12W).

[0258] In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every two months (Q8W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every three months (Q12W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every four months (Q16W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every five months (Q20W). In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every six months (Q24W).

[0259] In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to a subject about every two weeks to every three months or longer.

[0260] In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to the subject every one to three months, including any combination thereof (e.g., the antibody is administered to the subject in a first set of doses (induction) every month, followed by maintenance doses every two months; the antibody is administered to the subject in a first set of doses (induction) every month, followed by maintenance doses every three months; the antibody is administered to the subject in a first set of doses (induction) every two months, followed by maintenance doses every month; the antibody is administered to the subject in a first set of doses (induction) every two months, followed by maintenance doses every three months; the antibody is administered to the subject in a first set of doses (induction) every three months, followed by maintenance doses every month; the antibody is administered to the subject in a first set of doses (induction) every three months, followed by maintenance doses every two months; etc.).

[0261] In some embodiments, the second dose is administered about 1 week after the first dose is administered. In some embodiments, the second dose is administered about 2 weeks after the first dose is administered. In some embodiments, the second dose is administered about 3 weeks after the first dose is administered. In some embodiments, the second dose is administered about 4 weeks (one month) after the first dose is administered. In some embodiments, the second dose is administered about 5 weeks after the first dose is administered. In some embodiments, the second dose is administered about 6 weeks after the first dose is administered. In some embodiments, the second dose is administered about 7 weeks after the first dose is administered. In some embodiments, the second dose is administered about 8 weeks (two months) after the first dose is administered. In some embodiments, the second dose is administered about 9 weeks after the first dose is administered. In some embodiments, the second dose is administered about 10 weeks after the first dose is administered. In some embodiments, the second dose is administered about 11 weeks after the first dose is administered. In some embodiments, the second dose is administered about 12 weeks (three months) after the first dose is administered. In some embodiments, the second dose is administered about 13 weeks after the first dose is administered. In some embodiments, the second dose is administered about 14 weeks after the first dose is administered.

[0262] In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to the subject for one, two, three, four, five, six, twelve, twenty-four, forty-eight or more months.

[0263] In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to the subject at the same dose at each administration.

[0264] In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to the subject at a dose of 1.2 mg every month for three or more doses.

[0265] In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to the subject at a dose of 3.5 mg every month for three or more doses.

[0266] In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to the subject at a dose of 10 mg every month for three or more doses.

[0267] In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to the subject at a dose of 1.2 mg twice a month for three or more doses.

[0268] In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to the subject at a dose of 3.5 mg twice a month for three or more doses.

[0269] In some embodiments, the dosage form comprising the anti-fibrin antibody is administered to the subject at a dose of 10 mg twice a month for three or more doses.

[0270] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be about 1 mg, 1.2 mg, 2 mg, 2.5 mg, 3.5 mg, 5 mg, 7.5 mg, 10 mg, 12 mg, 15 mg, or 20 mg (e.g., to each eye) so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0271] The specific dose can be a uniform dose for each patient of about 1 mg, 1.2 mg, 2 mg, 2.5 mg, 3.5 mg, 5 mg, 7.5 mg, 10 mg, 12 mg, or 15 mg (e.g., to each eye) of anti-fibrin antibody.

[0272] In some embodiments, a dosage of from 1 mg / eye to 40 mg / eye of the anti-fibrin antibody is administered to a subject over a month (e.g., a 30 day drug cycle). As will be understood by one of skill in the art, a ‘monthly’ drug cycle is synonymous with a ‘30 day’ drug cycle or a ‘four week’ drug cycle. Similarly, as used herein, ‘Q8W’ (every eight weeks) is used interchangeably herein with ‘two months’ or ’60 days’; and ‘Q12W’ (every twelve weeks) is used interchangeably with ‘three months’, etc. In some embodiments, the dosage is administered one time over the month. In some embodiments, the dosage is administered two times over the month. In some embodiments, the dosage is administered three times over themonth. In some embodiments, the dosage is administered four times over the month. In some embodiments, each dose of the anti-fibrin antibody administered to the subject over the month is 1 mg, 1.2 mg, 2.5 mg, 3.5 mg, 5 mg, 7.5 mg, 10 mg, 12 mg, or 15 mg.

[0273] In some embodiments, a dosage of 1 mg / eye to 40 mg / eye of the anti-fibrin antibody is administered to a subject over two months (e.g., a 60 day drug cycle). In some embodiments, the dosage is administered one time over the two months. In some embodiments, the dosage is administered two times over the two months. In some embodiments, the dosage is administered three times over the two months. In some embodiments, the dosage is administered four times over the two months. In some embodiments, the dosage is administered five times over the two months. In some embodiments, the dosage is administered six times over the two months. In some embodiments, the dosage is administered seven times over the two months. In some embodiments, the dosage is administered eight times over the two months. In some embodiments, each dose of the anti-fibrin antibody administered to the subject over the two months is 1 mg, 1.2 mg, 2.5 mg, 3.5 mg, 5 mg, 7.5 mg, 10 mg, 12 mg, or 15 mg.

[0274] In some embodiments, a dosage of 1 mg / eye to 40 mg / eye of the anti-fibrin antibody is administered to a subject over three months (e.g., a 90 day drug cycle). In some embodiments, the dosage is administered one time over the three months. In some embodiments, the dosage is administered two times over the three months. In some embodiments, the dosage is administered three times over the three months. In some embodiments, the dosage is administered four times over the three months. In some embodiments, the dosage is administered five times over the three months. In some embodiments, the dosage is administered six times over the three months. In some embodiments, the dosage is administered seven times over the three months. In some embodiments, the dosage is administered eight times over the three months. In some embodiments, the dosage is administered nine times over the three months. In some embodiments, the dosage is administered ten times over the three months. In some embodiments, the dosage is administered eleven times over the three months. In some embodiments, the dosage is administered twelve times over the three months. In some embodiments, each dose of the anti-fibrin antibody administered to the subject over the three months is 1 mg, 1.2 mg, 2.5 mg, 3.5 mg, 5 mg, 7.5 mg, 10 mg, 12 mg, or 15 mg.

[0275] In some embodiments, a dosage of 1 mg / eye to 40 mg / eye of the anti-fibrin antibody is administered to a subject over four months (e.g., a 120 day drug cycle). In someembodiments, the dosage is administered one time over the four months. In some embodiments, the dosage is administered two times over the four months. In some embodiments, the dosage is administered three times over the four months. In some embodiments, the dosage is administered four times over the four months. In some embodiments, the dosage is administered five times over the four months. In some embodiments, the dosage is administered six times over the four months. In some embodiments, the dosage is administered seven times over the four months. In some embodiments, the dosage is administered eight times over the four months. In some embodiments, the dosage is administered nine times over the four months. In some embodiments, the dosage is administered ten times over the four months. In some embodiments, the dosage is administered eleven times over the four months. In some embodiments, the dosage is administered twelve times over the four months. In some embodiments, the dosage is administered thirteen times over the four months. In some embodiments, the dosage is administered fourteen times over the four months. In some embodiments, the dosage is administered fifteen times over the four months. In some embodiments, the dosage is administered sixteen times over the four months. In some embodiments, each dose of the anti-fibrin antibody administered to the subject over the four months is 1 mg, 1.2 mg, 2.5 mg, 3.5 mg, 5 mg, 7.5 mg, 10 mg, 12 mg, or 15 mg.

[0276] In some embodiments, maintenance doses of the anti-fibrin antibody are administered to a subject following a 30-, 60-, 90-, or 120-day drug cycle. In some embodiments, each maintenance dose of the anti-fibrin antibody administered to the subject is 1 mg / eye to 40 mg / eye. In some embodiments, each maintenance dose is administered every two, three, four, five, six, seven, or eight weeks or more. In some embodiments, each maintenance dose is administered every two weeks. In some embodiments, each maintenance dose is administered every four weeks. In some embodiments, each maintenance dose is administered every six weeks. In some embodiments, each maintenance dose is administered every eight weeks. In some embodiments, each maintenance dose is administered every twelve weeks.

[0277] In some embodiments, maintenance doses are administered throughout the remainder of the subject’s life.

[0278] Alternatively, a patient’s dose can be tailored to the approximate body weight or surface area of the patient. Other factors in determining the appropriate dosage can include the disease or condition to be treated or prevented, the severity of the disease, the route ofadministration, and the age, sex and medical condition of the patient. Further refinement of the calculations necessary to determine the appropriate dosage for treatment is routinely made by those skilled in the art, especially in light of the dosage information and assays disclosed herein. The dosage can also be determined through the use of known assays for determining dosages used in conjunction with appropriate dose-response data. An individual patient's dosage can be adjusted as the progress of the disease is monitored. Blood levels of the targetable construct or complex in a patient can be measured to see if the dosage needs to be adjusted to reach or maintain an effective concentration. Pharmacogenomics may be used to determine which targetable constructs and / or complexes, and dosages thereof, are most likely to be effective for a given individual (Schmitz et al., Clinica Chimica Acta 308: 43-53, 2001; Steimer et al., Clinica Chimica Acta 308: 33-41, 2001).

[0279] Anti-fibrin antibodies of the disclosure can be used alone or in combination with other agents that treat retinitis pigmentosa, age-related macular degeneration, glaucoma, diabetic retinopathy (e.g., diabetic macular edema), uveitis, and retinal detachment or symptoms associated therewith, or in combination with other types of treatment to treat, prevent, and / or reduce the risk of any disorders or conditions of the eye. In combination treatments, the dosages of one or more of the therapeutic compounds may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6, 2005). In this case, dosages of the compounds when combined should provide a therapeutic effect.Pharmaceutical Compositions

[0280] The present application provides compositions comprising the antibodies including pharmaceutical compositions comprising any one or more of the antibodies described herein with one or more pharmaceutically acceptable excipients. In some embodiments the composition is sterile. The pharmaceutical compositions generally comprise an effective amount of an antibody.

[0281] These compositions can comprise, in addition to one or more of the antibodies disclosed herein, a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material can depend on the route of administration, e.g., intravenous, subcutaneous,intrathecal, intraocular, cutaneous or subcutaneous, nasal, intramuscular, and intraperitoneal routes.

[0282] For intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection. Preservatives, stabilizers, buffers, antioxidants and / or other additives can be included, as required.

[0283] The anti-fibrin antibody that is to be given to an individual, administration is preferably in a “therapeutically effective amount” or “prophylactically effective amount” (as the case can be, although prophylaxis can be considered therapy), this being sufficient to show benefit to the individual. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of protein aggregation disease being treated. Prescription of treatment, e.g., decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above are found in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed), 1980.

[0284] A composition can be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.Methods of Use

[0285] In some embodiments, the present application provides methods of contacting fibrin with an anti-fibrin antibody, such as a human or humanized antibody, which results in inhibition of microglial and / or macrophage adhesion to the fibrin yC or fibrinogen yC domain. In some embodiments, the present application also provides such methods further comprising administering, in addition to an anti-fibrin antibodies described herein, an effective amount of a second therapeutic agent.

[0286] In some embodiments, the present application provides methods of using the isolated anti-fibrin antibodies described herein for treatment of a disorder or condition of the eye. In some embodiments, described herein is a method for treating a disorder or condition of the eye, the method comprising administering to a mammalian subject a therapeuticallyeffective amount of an anti-fibrin antibody or pharmaceutical composition comprising an anti-fibrin antibody described herein. In some embodiments, the present application provides methods of treating a disorder or condition of the eye selected from the group consisting of: retinitis pigmentosa, age-related macular degeneration, glaucoma, diabetic retinopathy (e.g., diabetic macular edema), uveitis, and retinal detachment. In some embodiments, the present application also provides such methods further comprising administering, in addition to an anti-fibrin antibodies described herein, an effective amount of a second therapeutic agent.

[0287] In some embodiments, described herein are methods for treating a pathology associated with fibrin binding to cell surface molecules CD1 lb / CD18 (Mac-1) and / or CD1 lc / CD18, the method comprising administering to a mammalian subject a therapeutically effective amount an isolated anti-fibrin antibody or a pharmaceutical composition comprising an isolated anti-fibrin antibody described herein. In some embodiments, the present application also provides such methods further comprising administering, in addition to an anti-fibrin antibodies described herein, an effective amount of a second therapeutic agent.

[0288] In some embodiments, described herein are methods of inhibiting microglia and / or macrophage activation, the method comprising administering to a mammalian subject a therapeutically effective amount an isolated anti-fibrin antibody or a pharmaceutical composition comprising an isolated antibody described herein. In some embodiments, the present application also provides such methods further comprising administering, in addition to an anti-fibrin antibodies described herein, an effective amount of a second therapeutic agent.

[0289] In some embodiments, described herein is a method of preventing a disorder or condition of the eye, the method comprising administering to a mammalian subject a therapeutically effective amount an isolated anti-fibrin antibody or a pharmaceutical composition comprising an isolated anti-fibrin antibody described herein. In some embodiments, the present application provides methods of preventing a disorder or condition of the eye selected from the group consisting of: retinitis pigmentosa, age-related macular degeneration, glaucoma, diabetic retinopathy (e.g., diabetic macular edema), uveitis, and retinal detachment. In some embodiments, the present application also provides such methods further comprising administering, in addition to an anti-fibrin antibodies described herein, an effective amount of a second therapeutic agent.

[0290] Also described herein, in some embodiments, are methods of treating a disorder or condition of the eye in a subject in need thereof, the method comprising administering to the subject a dosage form comprising an isolated antibody that binds human fibrin yC or fibrinogen yC domain, wherein the dosage form comprises the isolated antibody at a concentration of from about 20 mg / mL to about 200 mg / mL, and wherein the isolated antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein, respectively: CDR-H1 comprises the sequence set forth in SEQ ID NOs: 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181, 193, 205, 217, or 229; CDR-H2 comprises the sequence set forth in SEQ ID NOs: 2, 14, 26, 38, 50, 62, 74, 86, 98, 110, 122, 134, 146, 158, 170, 182, 194, 206, 218, or 230; CDR-H3 comprises the sequence set forth in SEQ ID NOs: 3, 15, 27, 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 159, 171, 183, 195, 207, 219, or 231; CDR-Ll comprises the sequence set forth in SEQ ID NOs: 4, 16, 28, 40, 52, 64, 76, 88, 100, 112, 124, 136, 148, 160, 172, 184, 196, 208, 220, or 232; CDR-L2 comprises the sequence set forth in SEQ ID NOs: 5, 17, 29, 41, 53, 65, 77, 89, 101, 113, 125, 137, 149, 161, 173, 185, 197, 209, 221, or 233; and CDR-L3 comprises the sequence set forth in SEQ ID NOs: 6, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, or 234.

[0291] Also described herein, in some embodiments, are methods of treating a disorder or condition of the eye in a subject in need thereof, the method comprising administering to the subject a dosage form comprising a means for binding human fibrin yC or fibrinogen yC domain, wherein the dosage form comprises the means for binding human fibrin yC or fibrinogen yC domain at a concentration of from about 20 mg / mL to about 200 mg / mL. As described herein, a means for binding human fibrin yC or fibrinogen yC domain is, in some embodiments, an anti-fibrin antibody or antigen-binding fragment thereof.

[0292] Also described herein, in some embodiments, are methods of treating a disorder or condition of the eye in a subject in need thereof, the method comprising administering to the subject one or more doses of a dosage form comprising an isolated antibody that binds human fibrin yC or fibrinogen yC domain, each dose selected from about 1 mg to about 20 mg to each eye of the isolated antibody, wherein the isolated antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light(VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein, respectively: CDR-H1 comprises the sequence set forth in SEQ ID NOs: 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181, 193, 205, 217, or 229; CDR-H2 comprises the sequence set forth in SEQ ID NOs: 2, 14, 26, 38, 50, 62, 74, 86, 98, 110, 122, 134, 146, 158, 170, 182, 194, 206, 218, or 230; CDR-H3 comprises the sequence set forth in SEQ ID NOs: 3, 15, 27, 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 159, 171, 183, 195, 207, 219, or 231; CDR-L1 comprises the sequence set forth in SEQ ID NOs: 4, 16, 28, 40, 52, 64, 76, 88, 100, 112, 124, 136, 148, 160, 172, 184, 196, 208, 220, or 232; CDR-L2 comprises the sequence set forth in SEQ ID NOs: 5, 17, 29, 41, 53, 65, 77, 89, 101, 113, 125, 137, 149, 161, 173, 185, 197, 209, 221, or 233; and CDR-L3 comprises the sequence set forth in SEQ ID NOs: 6, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, or 234.

[0293] Also described herein, in some embodiments, are methods of treating a disorder or condition of the eye in a subject in need thereof, the method comprising administering to the subject one or more doses of a dosage form comprising a means for binding human fibrin yC or fibrinogen yC domain, each dose selected from about 1 mg to about 20 mg to each eye of the means for binding human fibrin yC or fibrinogen yC domain.

[0294] Also described herein, in some embodiments, is a dosage form comprising an isolated antibody that binds human fibrin yC or fibrinogen yC domain for use in the treatment of a disorder or condition of the eye in a subject in need thereof, the use comprising administering to the subject one or more doses of the dosage form, each dose selected from about 1 mg to about 20 mg to each eye of the isolated antibody, wherein the isolated antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein, respectively: (a) CDR-H1 comprises the sequence set forth in SEQ ID NOs: 157, 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 169, 181, 193, 205, 217, or 229; (b) CDR-H2 comprises the sequence set forth in SEQ ID NOs: 158, 2, 14, 26, 38, 50, 62, 74, 86, 98, 110, 122, 134, 146, 170, 182, 194, 206, 218, or 230; (c) CDR-H3 comprises the sequence set forth in SEQ ID NOs: 159, 3, 15, 27, 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 171, 183, 195, 207, 219, or 231; (d) CDR-L1 comprises the sequence set forth in SEQ ID NOs: 160, 4, 16, 28, 40, 52, 64, 76, 88, 100, 112, 124, 136, 148, 172, 184, 196, 208, 220, or 232; (e) CDR-L2 comprises the sequence set forth in SEQ ID NOs: 161, 5, 17,29, 41, 53, 65, 77, 89, 101, 113, 125, 137, 149, 173, 185, 197, 209, 221, or 233; and (f) CDR- L3 comprises the sequence set forth in SEQ ID NOs: 162, 6, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 174, 186, 198, 210, 222, or 234.

[0295] Also described herein, in some embodiments, is a method of treating diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the method comprising intravitreally administering to the subject a dosage form comprising an isolated antibody that binds human fibrin yC or fibrinogen yC domain, wherein the dosage form comprises the isolated antibody at a concentration of about 100 mg / mL, and wherein the isolated antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein, respectively: (a) CDR-H1 comprises the sequence set forth in SEQ ID NO: 157; (b) CDR-H2 comprises the sequence set forth in SEQ ID NOs: 158; (c) CDR-H3 comprises the sequence set forth in SEQ ID NOs: 159; (d) CDR-L1 comprises the sequence set forth in SEQ ID NOs: 160; (e) CDR-L2 comprises the sequence set forth in SEQ ID NOs: 161; and (f) CDR-L3 comprises the sequence set forth in SEQ ID NOs: 162.

[0296] Also described herein, in some embodiments, is a method of treating diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the method comprising intravitreally administering to the subject a dosage form comprising a means for binding human fibrin yC or fibrinogen yC domain, wherein the dosage form comprises the means for binding human fibrin yC or fibrinogen yC domain at a concentration of about 100 mg / mL.

[0297] Also described herein, in some embodiments, is a method of treating diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the method comprising intravitreally administering to the subject one or more doses of a dosage form comprising an isolated antibody that binds human fibrin yC or fibrinogen yC domain, each dose selected from about 1.2 mg, about 3.5 mg, and about 10 mg to each eye of the isolated antibody, wherein the isolated antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein, respectively: (a) CDR-H1 comprises the sequence set forth in SEQ ID NO: 157; (b) CDR-H2 comprises thesequence set forth in SEQ ID NOs: 158; (c) CDR-H3 comprises the sequence set forth in SEQ ID NOs: 159; (d) CDR-L1 comprises the sequence set forth in SEQ ID NOs: 160; (e) CDR-L2 comprises the sequence set forth in SEQ ID NOs: 161; and (f) CDR-L3 comprises the sequence set forth in SEQ ID NOs: 162.

[0298] Also described herein, in some embodiments, is a method of treating diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the method comprising intravitreally administering to the subject one or more doses of a dosage form comprising a means for binding human fibrin yC or fibrinogen yC domain, each dose selected from about 1.2 mg, about 3.5 mg, and about 10 mg to each eye of the means for binding human fibrin yC or fibrinogen yC domain.

[0299] Also described herein, in some embodiments, is a dosage form comprising an isolated antibody that binds human fibrin yC or fibrinogen yC domain for use in the treatment of diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the use comprising intravitreally administering to the subject the dosage form, wherein the dosage form comprises the isolated antibody at a concentration of about 100 mg / mL, and wherein the isolated antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein, respectively: (a) CDR-H1 comprises the sequence set forth in SEQ ID NO: 157; (b) CDR-H2 comprises the sequence set forth in SEQ ID NOs: 158; (c) CDR-H3 comprises the sequence set forth in SEQ ID NOs: 159; (d) CDR-L1 comprises the sequence set forth in SEQ ID NOs: 160; (e) CDR-L2 comprises the sequence set forth in SEQ ID NOs: 161; and (f) CDR-L3 comprises the sequence set forth in SEQ ID NOs: 162.

[0300] Also described herein, in some embodiments, is a dosage form comprising an isolated antibody that binds human fibrin yC or fibrinogen yC domain for use in the treatment of diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the use comprising intravitreally administering to the subject one or more doses of the dosage form, each dose selected from about 1.2 mg, about 3.5 mg, and about 10 mg to each eye of the isolated antibody, wherein the isolated antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein,respectively: (a) CDR-H1 comprises the sequence set forth in SEQ ID NO: 157; (b) CDR-H2 comprises the sequence set forth in SEQ ID NOs: 158; (c) CDR-H3 comprises the sequence set forth in SEQ ID NOs: 159; (d) CDR-L1 comprises the sequence set forth in SEQ ID NOs: 160; (e) CDR-L2 comprises the sequence set forth in SEQ ID NOs: 161; and (f) CDR-L3 comprises the sequence set forth in SEQ ID NOs: 162.Combination Therapies

[0301] The methods and anti-fibrin antibodies described herein can be used alone or in combination with other therapeutic agents and / or modalities. The term administered “in combination,” as used herein, is understood to mean that two (or more) different treatments are delivered to the subject during the course of the subject’s affliction with the disorder, such that the effects of the treatments on the patient overlap at a point in time. In some embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent delivery.” In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. In some embodiments, delivery is such that the reduction of a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive.

[0302] Contemplated herein are combination therapies including administration of an anti-fibrin antibody described herein as one or more anti-vascular endothelial growth factor (VEGF) antibodies or antigen-binding fragments thereof. In some embodiments, anti-VEGF antibodies include, but are not limited to, Aflibercept (Zaltrap or Eylea) and biosimilars thereof (e.g., SB 15), Ranibizumab (Lucentis) and biosimilars thereof (e.g., XIMLUCI® (XSB-001), CIMERLI™ (ranibizumab -eqm), ONGAVIA, and SUSVIMO), Bevacizumab (Avastin) and biosimilars thereof (e.g., SB11, ABEVMY, ZIRABEV, ALYMSYS, VEGZELMA, FYB201 / RANOPTO, and AVZIVI), IBI302 (Efdamrofusp Alfa) and biosimilars thereof, and faricimab-svoa (VABYSMO) and biosimilars thereof.Methods of Administration

[0303] In some embodiments, the methods provided herein are useful for the treatment of a disorder or condition of the eye in an individual. In an embodiment, the individual is a human and the antibody is a fibrin antibody described herein.

[0304] In some embodiments, an antibody is administered intravitreally, subconjunctivally, retrobulbarly, intracamerally, intravenously, intramuscularly, subcutaneously, topically, intraperitoneally, intraorbitally, by implantation, or intraventricularly. In some embodiments, an antibody is administered intravitreally. An effective amount of an anti-fibrin antibody may be administered for the treatment of a disorder or condition of the eye comprising retinitis pigmentosa, age-related macular degeneration, glaucoma, diabetic retinopathy (e.g., diabetic macular edema), uveitis, and retinal detachment. The appropriate dosage of the anti-fibrin antibody may be determined based on the type of disease or disorder to be treated, the type of the anti-fibrin antibody, the severity and course of the disease or disorder, the clinical condition of the individual, the individual’s clinical history and response to the treatment, and the discretion of the attending physician.

[0305] In some embodiments, an antibody provided herein is administered with at least one additional therapeutic agent. Any suitable additional therapeutic or immunotherapeutic agent may be administered with an antibody provided herein. Additional therapeutic agents include agents that are used to treat or prevent a disorder or condition of the eye selected from the group consisting of: retinitis pigmentosa, age-related macular degeneration, glaucoma, diabetic retinopathy (e.g., diabetic macular edema), uveitis, and retinal detachment.

[0306] The additional therapeutic agent can be administered by any suitable means. In some embodiments, an antibody provided herein and the additional therapeutic agent are included in the same pharmaceutical composition. In some embodiments, an antibody provided herein and the additional therapeutic agent are included in different pharmaceutical compositions.

[0307] In embodiments where an antibody provided herein and the additional therapeutic agent are included in different pharmaceutical compositions, administration of the antibody can occur prior to, simultaneously, and / or following, administration of the additional therapeutic agent. In some embodiments, administration of an antibody provided herein and the additional therapeutic agent occur within about one month of each other. In someembodiments, administration of an antibody provided herein and the additional therapeutic agent occur within about one week of each other. In some embodiments, administration of an antibody provided herein and the additional therapeutic agent occur within about one day of each other. In some embodiments, administration of an antibody provided herein and the additional therapeutic agent occur within about twelve hours of each other. In some embodiments, administration of an antibody provided herein and the additional therapeutic agent occur within about one hour of each other.Kits and Articles of Manufacture

[0308] The present application provides kits comprising any one or more of the antibody compositions described herein. In some embodiments, the kits further contain a component selected from any of secondary antibodies, reagents for immunohistochemistry analysis, pharmaceutically acceptable excipient and instruction manual and any combination thereof. In one specific embodiment, the kit comprises a pharmaceutical composition comprising any one or more of the antibody compositions described herein, with one or more pharmaceutically acceptable excipients.

[0309] The present application also provides articles of manufacture comprising any one of the antibody compositions or kits described herein. Examples of an article of manufacture include vials (including sealed vials).EXAMPLES

[0310] Below are examples of specific embodiments for carrying out the present disclosure. The examples are offered for illustrative purposes only, and are not intended to limit the scope of the present disclosure in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should, of course, be allowed for.

[0311] The practice of the present disclosure will employ, unless otherwise indicated, conventional methods of protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. See, e.g., T.E. Creighton, Proteins: Structures and Molecular Properties (W.H. Freeman and Company, 1993); A.L. Lehninger, Biochemistry (Worth Publishers, Inc., current addition);Sambrook, et al., Molecular Cloning: A Laboratory Manual (2nd Edition, 1989); Methods In Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.); Remington'sPharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry 3rdEd. (Plenum Press) Vols A and B(1992).Example 1: Diabetic Retinopathy and Wet Age-Related Macular Degeneration Tissues Display High Levels of Fibrin Deposition and Associated Increase in Activation of Innate Immune Cells

[0312] This Example describes the levels of fibrin deposition and associated increases in activation of innate immune cells in diabetic retinopathy (DR) and wet age-related macular degeneration (AMD) tissues.Materials and MethodsTissue

[0313] Whole eyes (minus the cornea) were obtained from subjects having disorders or conditions of the eye listed in Table 4. Eyes were paraformaldehyde fixed, bisected, and formalin-fixed paraffin-embedded.Table 4: Eye samplesHistology

[0314] Immunohistochemistry (IHC) staining was done with the Leica Bond Polymer Refine Red Detection Kit (#DS9390) on the Leica Bond RX automated Stainer (Leica, Dear Park, IL) with the following protocol: 1) Primary incubation 15 min., 2) post primary alkaline-phosphatase linker 20 min., 3) alkaline-phosphatase polymer, 30 min, 4) red refine chromogen (10 + 5 min.) and 5) hematoxylin counter stain, 5 min. Tissue sections were stained separately for three markers of interest: 1) IBA1, a marker for microglia and macrophages, 2) iNOS, a marker of macrophage and microglial activation, and 3) fibrin plus isotype controls. Separate sections were also stained with hematoxylin and eosin (H&E), and good quality of the eye preparations were observed via the H&E stains.Results

[0315] H&E staining showed leaky blood vessels in a diabetic patient with wet AMD, but not in a healthy control. Fibrin deposits were present in eyes with diabetic retinopathy. Furthermore, in DR subjects, pathological hallmarks of DR tissue were observed, including wrinkling of the internal limiting membrane between the choroid and the retina. There was higher iNOS and Ibal staining in the retinas of DR patients compared to the normal controls. Furthermore, fibrin was increased in the choroid compared to the normal eye, in both vasculature and leakage from vasculature.

[0316] In a healthy control subject, in contrast, little staining for macrophages and minimal diffuse staining for insoluble fibrin were observed with no indication of a substantial fibrin network. Another healthy subject also showed minimal staining for insoluble fibrin.

[0317] Taken together, these experiments demonstrated that greater fibrin deposition in the choroid of subjects with diabetic retinopathy (n=3) and wet age-related macular edema (n=l) compared to normal controls (n=2). Increased microglia / macrophage activation (Ibal / iNOS) staining was also observed in the diseased retinas. The results presented here support the use of anti-fibrin antibodies described herein to treat diabetic retinopathy, diabetic macular edema, and age-related macular edema.Example 2: Anti-Fibrin P2 Treatment Decreases Inflammation in Uveitis ModelMaterials and Methods

[0318] Antigens were biotinylated using the EZ-Link Sulfo-NHS-Biotinylation Kit from Pierce. Goat F(ab')2 anti-human kappa-FITC (LC-FITC), ExtrAvidin-PE (EA-PE), and Streptavidin-AF633 (SA-633) were obtained from Southern Biotech, Sigma, and Molecular Probes, respectively. Goat anti-human IgG-PE (Human-PE) was obtained from Southern Biotech. Anti-Mouse APC was obtained from Jackson ImmunoResearch.

[0319] Experimental autoimmune uveitis (EAU) is an organ-specific autoimmune disease that targets the neural retina. This autoimmune response is induced when animals are immunized with retinal antigens (interphotoreceptor retinoid-binding protein (IRBP), in this case). In order to confirm therapeutic role of anti-fibrin treatment in inflammatory eye conditions or diseases, the efficacy of the anti-fibrin affinity matured antibodies were tested in a rat EAU model after intravitreal administration of the anti-fibrin antibodies.

[0320] In this study, 52 Lewis rats were divided into six groups, namely PBS (Group 1), Isotype control (Group 2), ADI-60143 low dose (Group 3), ADI-60143 high dose (Group 4),FTY-720 positive control (Group 5), and Naive (Group 6). Animals from all groups, except Group 6, were immunized with an emulsion of IRBP in Complete Freund’s Adjuvant (CFA) on Day 0. Similarly, animals from Group 1-4 received a single intravitreal injection of sponsors test article once on Day 0. Animals in Group 5 received once daily oral administration of positive control FTY-720. After a period of 8-10 days, immunized animals developed uveitis in each eye. Clinical evaluations were performed for all the animals at baseline, day 4, 7, 11, and 14 to follow the extent of diseases developed. Clinical observations were performed as follows:Frequency. Once on each study day.Procedure -. Groups were randomized ahead of evaluations to keep the examiner masked. Animals were observed under a dissection microscope and scored on a scale of 0-4 based on their anterior clinical disease. Photographs of the anterior chamber were taken at the time of clinical evaluations.Clinical observation scoring'.0-0.5: No disease; eye is translucent. Some blood vessels in the iris may be dilated.1 : Engorged blood vessels in iris; abnormal pupil contraction (or dilation).2: Slight haziness to the anterior chamber.3: Moderately opaque anterior chamber, but pupil still visible.4: Opaque anterior chamber and obscured pupil.

[0321] All animals were euthanized on Day 14 and immediately following euthanasia, whole eyes (OU) were collected, Upon verification of death, both eyes of each animal were carefully removed. One eye was collected for histological analysis, and the other eye was collected for cytokine analysis. Eyes for cytokine analysis were hemisected and retina was collected. Each eye was carefully orientated for optimal microscopic examination prior to wax embedding. Sections (5 pm) were cut and stained with hematoxylin and eosin for histological examination and scoring according to the following scale summarized below and as described by Caspi, et al. (2012). Histological analysis was masked to the examiner.Clinical Scoring / Uveitis grading was determined as follows:0: No disease, normal retinal architecture.0.5: Trace. <1 / 4 Mild inflammatory cell infiltration of the retina with or without photoreceptor damage.1 : > % Mild inflammation and / or photoreceptor outer segment damage.2: > % Mild to moderate inflammation and / or lesion extending to the outer nuclear layer.3 : >lA Moderate to marked inflammation and or lesion extending to the inner nuclear layer.4: > % Severe inflammation and / or full-thickness retinal damage.

[0322] As shown in FIG. 1, rats administered a low or high dose of the murinized ADI- 60143 LALA Fc-stabilized antibody clone (mADI-60143 LALA) exhibited a significantly reduced clinical uveitis score on Day 14 of the study. These results confirm that the affinity matured anti-fibrin antibodies decreased inflammation in subjects with uveitis and are therapeutically effective in a pre-clinical model of eye conditions related to vascular defects of the eye, such as uveitis.Example 3: Anti-Fibrin P2 Treatment Ameliorates Vascular Leakage and Lesion Size in Macular Degeneration Model

[0323] Laser-induced choroidal neovascularization (LCNV) was generated in 6- to 8- week-old Brown Norway rats on experiment Day 0. Animals were anesthetized with an intraperitoneal (IP) injection of ketamine / xylazine, and topical administration of 1% tropicamide for pupillary dilation. Using a handheld cover slip as a contact lens and Gen Teal lubricating eye gel as a medium contacting the cover slip to the surface of the cornea, a Nidek GYC-500 green laser photocoagulator coupled to a Nidek SL-1800 slit lamp was used to create six lesions equidistant from the optic nerve head in the retinal mid periphery.

[0324] Laser parameters included: 532 nm wavelength, 100 pm spot size, 0.1 sec duration, and 120 mW. Anti-fibrin antibodies disclosed herein were administered via intravitreal (IVIT) injection on the same day as laser. 6 days post-laser, vascular leakage was assessed via quantitative fluorescein angiography (qFA). At 7 days post-laser, animals were sacrificed for choroidal neovascularization (CNV) area analysis.

[0325] On experiment Day 1, treatments were administered bilaterally via IVIT injection according to Table 5 below.Table 5

[0326] As qFA is a non-terminal (e.g., survival procedure) procedure, rats used for these readouts were also used for CNV area analysis, serum collection, and histology.

[0327] Animals were anesthetized with isoflurane and treated with topical proparacaine before injection to provide topical analgesia. IVIT injections of various doses (e.g., 8 pg / eye (low dose), 16 pg / eye (medium dose), and 50 pg / eye (high dose)) of mADI-60143 LALA or ADI-60143 LALA and up to 2.0 pL volume were tested and administered using a short barrel, 2 pL syringe with a custom made, detachable 33-gauge needle (Hamilton Co.) under an operating microscope (Zeiss Microscopy). After injection, neomyCin / polymyxin B / gramicidin ophthalmic drops were applied to prevent infection. Treatments were randomized between animals and housing cages.

[0328] In a first set of experiments, at experiment Day 6, vascular leakage was assessed via qFA (FIG. 2). In a second set of similar experiments, at experiment Day 7, Day 14, and Day 28, vascular leakage was assessed via qFA (FIG. 4). Animals were anesthetized with an IP injection of ketamine / xylazine. Sodium fluorescein was administered via tail vein injection at a dose of 500 mg / kg. Fluorescent fundus images were captured for one eye of each animal with a Micron IV imaging system at four minutes post-fluorescein injection, and again two minutes later. Imaged software was used by a masked observer to quantify the fluorescence intensity for one lesion per eye using the ‘integrated density’ function. The difference in integrated density between the two times post-injection was recorded as a readout of vascular leakage. As qFA is a survival procedure, animals were used for CNV area.

[0329] It was observed that the low, medium, and high doses of the anti-fibrin antibody were effective at Day 7 and Day 14 (FIG. 4, left and middle panels, respectively). The most noticeable effects were observed on Day 14 in the high dose group (see FIG. 4, middle panel, upward-pointing arrow). As expected, there was no significant effect seen at Day 28, since even the isotype control were healing on their own at that time point. (FIG. 4, right panel).

[0330] In the first set of experiments, at experiment Day 7, animals were euthanized and their eyes enucleated. In the second set of experiments, animals were euthanized at Day 28 or later. In both sets of experiments, the extent of CNV at the Bruch’s membrane rupture sites was measured by masked observers using computer-assisted image analysis of FITC- conjugated isolectin B4-stained choroidal flat-mounts. As the anti-fibrin antibody was administered to both eyes in the same animal, the areas for all lesions in both eyes of each animal was averaged and reported as a single data point (the results of the first set of experiments are presented in FIG. 3 and the results of the second set of experiments are presented in FIG. 5). Statistical analysis of area measurements were performed by ANOVA and a parametric post hoc test. Retinas were paraffin embedded and sectioned for further analysis.

[0331] It was observed that mADI-60143 LALA reduced lesion size on Days 7 and 15 and ADI-60143 LALA reduced lesion size on Day 28 (FIG. 5).

[0332] When similar experiments were conducted in a LCNV model of wet AMD in C57 / B6 mice (lasered in both eyes on Day 0, IVT injection within 30 minutes with control IgG 13 pg / eye, ADI-60143 LALA 13 pg / eye, or Aflibercept (Aflib) 10 pg / eye, which represent molar equivalents), and lesion size was measured, it was observed that IVT injection of ADI-60143 LALA reduced neovascular lesions (FIG 12).

[0333] Taken together, these experiments demonstrated that mADI-60143 LALA and ADI-60143 LALA were effective in a LCNV rat and mouse model of macular degeneration, as demonstrated by ameliorated vascular leakage and lesion size.Example 4: Anti-Fibrin P2 Treatment Effective in Diabetic Retinopathy Model

[0334] A murine model of streptozotocin (STZ)-induced diabetic retinopathy (DR) was used to evaluate the efficacy of a mADI-60143 LALA.

[0335] In brief, diabetes was induced with daily STZ injections. Weekly IP injections of an exemplary anti-fibrin antibody described herein, as well as an isotype control antibody were given to 3 groups: 1) nondiabetic, isotype control, 2) diabetic, isotype control and 3) diabetic, mADI-60143 LALA.

[0336] Vascular leakage was assessed via qFA. Animals were anesthetized with an IP injection of ketamine / xylazine. Sodium fluorescein was administered via tail vein injection at a dose of 500 mg / kg. Fluorescent fundus images were captured for one eye of each animal with a Micron IV imaging system at four minutes post-fluorescein injection, and again two minutes later. Imaged software was used by a masked observer to quantify the fluorescenceintensity for one lesion per eye using the ‘integrated density’ (IntDen) function. The difference in integrated density between the two times post-injection was recorded as a readout of vascular leakage.

[0337] It was observed that mADI-60143 LALA reduced vascular leakage (FIG. 6), indicating that mADI-60143 LALA was effective in a STZ rat model of DR.Example 5: Rat Dosing Informs Human Dosing of an Anti-Fibrin P2 Antibody for Treatment of Disorders or Conditions of the Eye

[0338] As described in Example 3, LCNV was generated in 6- to 8-week-old Brown Norway rats and IVIT injections of various doses (e.g., 8 pg / eye (low dose), 16 pg / eye (medium dose), and 50 pg / eye (high dose)) of ADI-60143 LALA were administered.

[0339] In result, it was observed that there was a statistically significant dose-dependent effect on Day 14 (FIG. 7, left panel). The reduction with 50 pg and 16 pg of ADI-60143 LALA was greater than that observed when a dose of 8 pg was administered (46%, 44%, and 65% relative to isotype, respectively). A similar trend is observed on Day 28 (FIG. 7, right panel) in about half of the eyes. Both 16 pg and 8 pg were less effective than the 50 pg dose. These results also suggested a loss of efficacy with time, as agent clears the eye.Modeling Human Dose

[0340] Eye size is generally proportional to body size. However, small rodent eyes are occupied by a larger relative lens volume and relatively smaller vitreous humor than larger mammals. A range of vitreous volume has been reported for different species. For example, it has been reported that rats have a vitreous volume of 0.013-0.054 mL; rabbits of 1.5-1.8 mL, monkeys of 1.8-2.0 mL, and humans of 4-5 mL. Based on the dose titration study discussed supra, the human doses based on molar equivalence after IVIT injection were calculated. Since the ADI-60143 LALA binding KD was the same for the rodent and human P2 inflammatory epitope (Table 6), no correction was needed for binding affinity. Calculations considered the rat vitreous volume at 0.02 and 0.05 mL and an effective dose of 50 pg (high) and 16 pg (low) based on the day 14 qFA results. Overall, the effective range in humans was estimated at 2.1 to 17 pM, corresponding to 1.3 mg / eye to 10 mg / eye.Table 6. Estimation of Human Equivalent DoseExample 6: Toxicology of Antibody Clone ADI-60143 LALA

[0341] This Example describes a dose range determination study to evaluate the potential toxicity, as well as systemic and serum toxicokinetics (TK), of IVT (ocular) administration of ADI-60143 LALA in rabbits and monkeys. The serum TK was characterized in monkeys, while the ocular and systemic TK of ADI-60143 LALA was characterized in rabbits. In addition, systemic toxicology studies were conducted by the IV route with ADI-60143 LALA in rats and monkeys. These studies included single-dose, and repeat-dose dose range-finding studies followed by 1 -month repeat-dose GLP studies with a recovery period and TK in rats and monkeys. Additionally, a tissue cross-reactivity study was conducted across rat, monkey, and human tissues. A list of the toxicology studies conducted with ADI-60143 LALA is shown in Table 7. ADI-60143, rather than ADI-60143 LALA, was used in an early non-GLP rat study.Table 7. Ocular and Systemic Toxicology Studies with ADI-60143 LALAIVT Toxicokinetics

[0342] In rabbits, systemic and ocular exposure were confirmed at the end of the study.The ocular and serum TK were evaluated from 2 female New Zealand white rabbits per timepoint or 4 eyes per timepoint at the following timepoints: 24, 72, 168, and 648 hours(study design detailed below). Systemic serum exposure after one IVT administration (Day 1) at 1.5 mg / eye (bilateral) at 648 hours post-dose was 7.55 pg / mL for Cmax and 981 h*pg / mL for AUCiast. Systemic serum exposure after two IVT administrations (Days 1 and 29) at 5 mg / eye on Day 43 was 26.8 pg / mL for Cmax and 8470 h*pg / mL for AUCiast. Following a single dose (Group 1) of 1.5 mg / eye, the Tmax in serum was observed at approximately 168 hours with a Cmax of 9.05 pg / mL and AUCiast at 648 hours of 981 h*pg / mL. ADI-60143 LALA serum levels were largely cleared by 672 hours after a single IVT injection of 1.5 mg / eye in the rabbit. Additional rabbits were given 2 doses on Days 1 and 29 at 1.5 mg / eye (Group 2) and 5 mg / eye (Group 3), which resulted in systemic Cmax serum concentrations of 8.44 and 26.8 pg / mL and AUCiast of 2130 and 8470 h*pg / mL, respectively, on Day 43 or 14 days after the 2ndIVT injection on Day 29 (Table 8). In conclusion, greater systemic exposure was observed following two IVT injections compared with a single IVT injection.Table 8. Serum ADI-60143 LALA PK Parameters in Rabbit Study 20436968 Following a Single IVT Bilateral Injection at 1.5 mg / eye or Two IVT Injections (Days 1 and 29 - Group 2 at 1.5 mg / eye and Group 3 at 5 mg / eye)**Abbreviations: AUCiast = area under the drug concentration versus time curve from time 0 to the time of the last measurable timepoint;Cmax maximum drug concentration;PK = pharmacokinetics; andTmax = time of occurrence for maximum drug concentration.* Group 1 : 10 animals: 2 each euthanized at day 2, 4, 7, 14, and 28; Groups 2 and 3: 3 animals each euthanized at day 43.** All parameters are presented as geometric mean (geometric CV%); number of observations, tmax and tlast are presented as median [min-max]; number of observations.Ocular Distribution of ADI-60143 LAL A in Rabbits Following IVT Injection

[0343] Exposure in the vitreous humor following a single IVT injection at 1.5 mg / eye was 817 pg / mL for Cmax and 183000 h*pg / mL for AUCiast; the exposures in the vitreous at 24 hours after one IVT injection were much higher (>30-times) than the exposures in the serum following two IVT injections at 1.5 or 5 mg / eye. Ocular tissue exposure was also confirmed in the aqueous humor, choroid / RPE, and retina following a single IVT injection at 1.5 mg / eye as summarized below in Table 9. The highest ADI-60143 LALA ocular tissue concentrations were seen in the following order (highest to lowest): vitreous humor » aqueous humor > choroid / RPE > retina. The ti / 2 in the rabbit vitreous was 114.6 hr or 4.78 days, which supported monthly dosing in the clinic.Table 9. PK Parameters in Rabbit Eye Tissue after Single IVT Injection at1.5 mg / eye*Abbreviations: AUCiast = area under the drug concentration versus time curve from time 0 to the time of the last measurable timepoint;Cmax maximum drug concentration;IVT = intravitreal;PK = pharmacokinetics;RPE = retina pigment epithelium;11 / 2 = half life; andTmax = time of occurrence for maximum drug concentration.* PK parameters used the average of 2 animals and 2 eyes (N=4 eyes per timepoint) to obtain the noncompartmental analysis.Single-Dose and Repeat-Dose Ocular Toxicology Study in Rabbits

[0344] This non-GLP study determined the potential toxicity and ocular distribution of ADI-60143 LALA when administered by single or repeat (two) ocular IVT injections followed by an observation period of up to 43 days in New Zealand white rabbits. In addition, the toxicokinetic characteristics of ADI-60143 LALA were determined. The study design is presented in Table 10.Table 10. Single and Repeat-Dose (2 Total Doses) IVT Ocular Toxicology Study in RabbitsAbbreviation: IVT = intravitreal.aBilateral IVT injections

[0345] The following parameters and endpoints were evaluated in this study: mortality, clinical observations, body weights, qualitative food evaluation, ophthalmology, tonometry, clinical pathology parameters (hematology, coagulation, and clinical chemistry), TK parameters, anti-drug antibody (ADA), macroscopic and microscopic examinations, and ocular tissue biodistribution.

[0346] There were no unscheduled deaths, test item-related clinical signs or changes in body weight or food consumption related to ADI-60143 LALA administration. Furthermore, there were no test item-related clinical pathology changes or intraocular pressure (IOP) changes as measured by tonometry or gross pathology changes.

[0347] Ophthalmology examinations did not reveal any test item-related changes at 1.5 mg / eye following one or two doses. At 5.0 mg / eye, all eyes developed a minimal number of cells in the vitreous humor, primarily following the second dose on Day 29.

[0348] Slight non-dose related decreases in IOP were noted unilaterally or bilaterally in some eyes primarily on Day 3 and occasionally on Day 14, thereafter recovering to pre-dose ranges. These changes were likely related to the experimental procedure, given the absence of significant ocular inflammation, the low incidence, and the timing in relation to dosing.

[0349] Microscopic findings were limited to eyes that received two injections of 5.0 mg / eye. Two animals (animal nos. 3501 and 3502) had mononuclear cell infiltrates in the vitreous (minimal to mild) and optic disc (minimal) that was characterized by a mix of lymphocytes, plasma cells, and macrophages. These changes correlated with the changes observed during the ophthalmology examination. Animal no. 3502 also had mildmononuclear cell infiltration in the peripheral, temporal, and nasal (dorsally only) choroid, extending into the adjacent subretinal space and ciliary body. Additionally, minimal multifocal retinal mononuclear cell infiltration was observed in this same dorsal area, as well as more dispersed in the eye, in association with minimal multifocal global retinal degeneration. All retinal layers were disorganized due to cell infiltration. A minimal focal dorsal, temporal, and nasal retinal detachment (with retinal pigmented epithelium hypertrophy) was also observed in the left eye for animal no. 3502.

[0350] Systemic and ocular exposure was confirmed at the end of the study. Ocular tissue exposure was also confirmed in the aqueous humor, choroid / retinal pigment epithelium (RPE), and retina following a single IVT injection at 1.5 mg / eye as summarized previously in Table 9. In summary, the highest ADI-60143 LALA ocular tissue concentrations were seen (from greatest to smallest) in the vitreous humor > aqueous humor > choroid / RPE > retina. The ti / 2 in the rabbit vitreous was 114.67 hours or 4.78 days, which supported monthly dosing in the clinic.

[0351] In conclusion, bilateral IVT injections of ADI-60143 LALA once or twice (one month apart) was well tolerated at 1.5 mg / eye. At 5.0 mg / eye, in vivo ocular changes were minimal, however mononuclear cell infiltrates primarily in the vitreous body and optic disc were observed in 3 / 3 eyes, and more extensive microscopic changes including retinal degeneration and focal detachment was seen in 1 / 3 eyes. ADI-60143 LALA was detected in the serum and distributed to ocular tissues (vitreous humor, aqueous humor, choroid / RPE, and retina) as expected. The ti / 2 in the rabbit vitreous was 114.67 hours or 4.78 days which supported monthly dosing in the clinic.Single-Dose Ocular Toxicology Study in Cynomolgus Monkeys

[0352] This non-GLP study determined the potential toxicity and biodistribution of ADI- 60143 LALA when given as a single-dose via ocular IVT administration to NHPs followed by a 30-day observation period. In addition, the TK characteristics of ADI-60143 LALA were determined. The study design is presented in Table 11.Table 11. Single-Dose IVT Ocular Toxicology Study in Cynomolgus MonkeysAbbreviation: IVT = intravitreal.aAnimals were dosed by a single dose IVT bilateral injection.cAnalytical results showed that all Dose Formulation samples collected on Day 1 were within ± 10% of target.

[0353] The following parameters and endpoints were evaluated in this study: mortality, clinical observations, body weights, appetence, ophthalmology exams, tonometry, electroretinography, clinical pathology parameters (hematology, coagulation, and clinical chemistry), TK parameters, anti-drug antibody, macroscopic and microscopic examinations.

[0354] There was no mortality, or changes in body weight, appetence, electroretinography, clinical pathology, or macroscopic or microscopic examinations related to administration of ADI-60143 LALA.

[0355] Single IVT administration of ADI-60143 LALA to cynomolgus monkeys was well tolerated at dose levels up to 5 mg / eye, with only minor findings characterized by a minimal amount of anterior chamber and vitreous cell-like opacities (vitreal cells) at all dose levels, including controls. On Day 3, mostly transient anterior chamber cells were seen in 4 / 8, 6 / 8, 7 / 8, and 5 / 8 eyes from animals receiving 0, 1.5, 3, and 5 mg / eye, respectively. This change was not dose-related as it resolved by Day 29 with only 1 / 8 eyes at both 1.5 and 5 mg / eye. Vitreal cells were also noted primarily in the ADI-60143 LALA-treated eyes on Day 3 (only 1 / 8 control eyes had them on Day 3 and Day 14). These vitreal cells were graded very slight to slight and were occasionally transient or late developing. By Day 29, the incidences but not the severity of vitreal cells was dose-related with 25%, 50%, and 88% of eyes affected at 1.5, 3, and 5 mg / eye, respectively. Due to the presence of cells in the anterior chamber and vitreous in a few eyes in the control up to Day 14, a minor effect of the vehicle could not be completely ruled out. Overall, these changes were considered minor and none of the eyes developed prominent inflammation.

[0356] There were no changes in IOP related to ADI-60143 LALA administration. Slight changes (increases and / or decreases) in IOP values that remained within an expected range were noted on each occasion without evidence of a dose dependent relationship.

[0357] Systemic and ocular exposure was confirmed at the end of the study. Systemic serum exposure after one IVT administration (Day 1) at 1.5 mg / eye at 672 hours post-dose was 16.2 pg / mL for Cmax and 8230 h*pg / mL for AUCiast. Systemic serum exposure after one IVT administration (Day 1) at 5 mg / eye at 672 hours post-dose was 48.6 pg / mL for Cmax and 24700 h*pg / mL for AUCiast. ADA analyses of serum samples were negative on Day 14. Mean vitreous humor concentrations on Day 30 following a single IVT injection ranged from 1.44 pg / mL at 1.5 mg / eye to 2.24 pg / mL at 3 mg / eye and 5.54 pg / mL at 5 mg / eye. Ocular tissue exposure was also confirmed in the retina following a single IVT injection.

[0358] In conclusion, the IVT administration of ADI-60143 LALA was well tolerated at a dose level of up to 5 mg / eye for 30 days post-administration with no significant ocular or systemic changes. Serum exposure at the highest tolerated dose of 5 mg / eye at 672 hours after a single dose was 48.6 pg / mL for Cmax and 24700 h*pg / mL for AUCiast.Repeat-Dose Ocular Toxicology Study in Cynomolgus Monkeys

[0359] The definitive repeat dose ocular toxicology GLP study was conducted in the cynomolgus monkey because primates have a macula, which is a cone-rich area of the retina, which is the same as humans. Therefore, the cynomolgus monkey was used in the repeat dose GLP ocular toxicology study. A thorough assessment of ocular toxicology was performed including ophthalmic exams, IOP, ERG, and ocular histopathology.

[0360] The GLP ocular toxicology study determined the potential toxicity and biodistribution of ADI-60143 LALA following IVT administration for 57 days (3 doses) to cynomolgus monkeys and evaluated the potential reversibility of any findings following an 8- week recovery period in order to support the proposed clinical trial. In addition, the TK characteristics of ADI-60143 LALA were determined. The study design is presented in Table 12Table 12. 57-Day Repeated-dose (3 Total Doses) IVT Ocular Toxicology Study in Cynomolgus Monkeys with 8-Week RecoveryAbbreviation: IVT = intravitreal.aTest and reference items were administered once monthly (Days 1, 29, and 57) via ocular intravitreal bilateral injections.

[0361] The following parameters and endpoints were evaluated in this study: mortality, clinical observations, body weights, appetence, ophthalmology examinations (funduscopic or indirect ophthalmoscopy and biomicroscopic or slit lamp examinations), tonometry, electroretinography (ERG), intraocular pressure (IOP), clinical pathology parameters (hematology, coagulation, and clinical chemistry), toxicokinetic parameters, anti-drug antibody (serum and vitreous humor), organ weights, macroscopic and microscopic examinations, ocular tissue analysis for ADI-60143 LALA concentration (left eye: retina, vitreous humor, and aqueous humor).

[0362] Ocular endpoints specifically included tonometry or IOP and ophthalmology examinations (funduscopic or indirect ophthalmoscopy) and biomicroscopic or slit lamp examinations once pre-study and again on Days 3, 15, 27, 31, 43, 55, 59, 67, 71, and 110 (Recovery Study only). Electroretinography (ERG) was evaluated on Days pre-study, and again on Days 22 and 69 (Main and Recovery Study, respectively) and Day 107 (Recovery Study only), and a thorough evaluation of ocular histopathology (including a full range of ocular tissues, including the macula) was conducted. The retina, vitreous humor, and aqueous humor were evaluated for ADI-60143 LALA levels.

[0363] There were no unscheduled deaths. There were no ADI-60143 LALA-related effects on clinical observations, body weight, food consumption, ophthalmology examinations, IOP, ERG, clinical pathology parameters (hematology, coagulation, and clinical chemistry), organ weights, or macroscopic or microscopic examinations.

[0364] Systemic and ocular exposure was confirmed at the end of the study. Systemic serum exposure following repeat IVT administrations on Day 57 (336 hours post-dose) at 1.5 mg / eye was 19.9 pg / mL for Cmax and 6010 h*pg / mL for AUCiast. Systemic serum exposurefollowing repeat IVT administrations on Day 57 (336 hours post-dose) at 5 mg / eye was 71.5 pg / mL for Cmax and 21700 h* pg / mL for AUCiast. Mean vitreous humor concentrations on Day 72 (15 days after the last dose on Day 57, following 3 once monthly IVT injections) ranged from 23.65 pg / mL at 1.5 mg / eye to 41.95 pg / mL at 3 mg / eye and 99.4 pg / mL at 5 mg / eye. At the end of the recovery period on Day 113, vitreous levels in recovery animals at 5 mg / eye had largely cleared to low levels of 0.04 pg / mL. Ocular tissue exposure was also confirmed in the retina and aqueous humor following a single IVT injection.

[0365] In conclusion, administration of ADI-60143 LALA once monthly (3 doses) via ocular IVT bilateral injections was well tolerated in cynomolgus monkeys at dose levels of 1.5, 3, or 5 mg / eye, with no significant systemic or ocular changes or microscopic findings at any dose level. In this study, the NOAEL was considered to be 5 mg / eye and serum exposure at the NOAEL on Day 57 was 71.5 pg / mL for Cmax and 21700 h*pg / mL for AUCiast.

[0366] Taking the results of all of the above described intravitreal studies in cynomolgus monkeys together, the results demonstrated that cynomolgus monkeys tolerated up to 5 mg / eye of ADI-60143 LALA in a single dose study. The NOAEL was 5 mg / eye, which provided an ocular safety margin of 10-fold over the proposed first-in-human (FIH) dose. The ocular safety margins are summarized in Table 13.Table 13. Ocular Safety Margins in Human Based on Dose Comparison (Vitreous Volume Scaling) to Cynomolgus MonkeyAbbreviations: IVT = intravitreal; andNA = not applicable.aVitreous volumes in monkey 2mL and human; 4.65 mL women and 4.97 mL in men; 4.8mL average vitreous volume used for calculations).bCalculated by dividing human vitreous volume by monkey vitreous volume and multiplying by the ADI-60143 LALA monkey dose per eye (pg).cCalculated by dividing the ADI-60143 LALA human equivalent dose in monkey by the ADI- 60143 LALA dose per eye in humans at the planned starting dose.dCalculated by dividing the ADI-60143 LALA human equivalent dose in monkey by the ADI- 60143 LALA dose per eye in humans at the highest anticipated clinical dose.eFIH clinical starting dose.fHighest anticipated clinical dose.Intravenous Route of Administration

[0367] A IV toxicology study was conducted to characterize the toxicity profile and identify safety margins for ADI-60143 LAL A. Single dose range-finding studies were conducted in rats and monkeys. These studies evaluated doses of up to 60 mg / kg in rats and up to 100 mg / kg in monkeys. All doses were well tolerated and there were no adverse effects observed in either study. Four-week repeated-dose GLP toxicology studies were conducted in rats at ADI-60143 LAL A doses of up to 100 mg / kg every 4 days (7 total doses) and in monkeys at weekly ADI-60143 LALA doses of up to 100 mg / kg (5 total doses). Additionally, a 5 -week GLP toxicology study was conducted in monkeys at weekly doses of up to 400 mg / kg (5 total doses). Safety pharmacology endpoints (CNS, CV, and respiratory) were incorporated into the toxicology studies. There were no effects on any safety pharmacology parameters evaluated. There were no ADI-60143 LALA-related mortalities, clinical signs, changes in body weight, clinical pathology (hematology, coagulation, clinical chemistry, and urinalysis), or ophthalmology in these studies. There were no ADI-60143 LALA-related macroscopic or microscopic findings. The NOAEL for the rat study was 100 mg / kg every 4 days for 4 weeks and the NOAELs from the monkey studies was 100 mg / kg once weekly for 4 weeks. Although no NOAEL was identified due to adverse multiorgan vasculitis observed in one male at 200 mg / kg, IHC confirmed that the systemic vasculitis was due to immune complex deposition and is therefore not considered translatable to humans. A summary of the exposures at the NOAEL doses and exposures are shown in Table 14.Table 14. Summary of Toxicology Study NOAELs For IV InjectionAbbreviations: AUC = area under the drug concentration versus time curve;Cmax maximum drug concentration;F = female;M = male; andNOAEL = no-observed-adverse-effect level.aValues from TK parameters measured on Day 25 in rats and Day 29 in monkeys. Rat 100 mg / kg AUCiast was calculated from last dose (Day 25) through Day 60. Monkey 100 mg / kg AUCO-72 was calculated from the last dose (Day 29) through 72 hours. Monkey 400 mg / kg AUCO-144 was calculated from the last dose (Day 29) through 144 hours. For the 26-week study, AUCo-168 was calculated from the last dose (Day 176) through 168 hours.bNo NOAEL was identified in this study. The adverse finding of multiorgan vasculitis in one 200 mg / kg male was a result of immune complex deposition and is not considered translatable to humans. Thus, there were no adverse findings in this study at weekly dose levels of up to 400 mg / kg that are of concern for human dosing.

[0368] Taken together, these results demonstrated that IV exposures were greater than the systemic exposures observed following IVT administration, approximately 246-times higher for Cmax and 82-times higher for AUC which further supports a low risk for the systemic safety of ADI-60143 LALA following IVT administration.Example 7: Effective Intravitreal ADI-60143 LALA Dose

[0369] The effective human IVT dose for ADI-60143 LALA was determined using nonclinical PK (rabbit and NHP) and dose efficacy studies (rat LCNV). One-compartment (1C; vitreous humor) and three-compartment (3C; retina, vitreous, and aqueous) models were applied. The 1C model assumed diffusion-controlled drug elimination from the vitreous. The ocular ti / 2 was directly proportional to the product of the hydrodynamic radius of the macromolecule (5.0 nm for IgG) and the square of the radius of the vitreous globe, which varies from ~24-fold (rat to human) to ~2-fold (rabbit to human). The model assumed monoexponential decay from the vitreous humor. The 3C model also depended on the hydrodynamic radius but also considered transport pathways from the vitreous to both the retina and aqueous chamber and clearance from the aqueous chamber. The model used fixed physical parameters for rabbit and human.

[0370] IVT kinetics (vitreous humor) usually follow a 1C model with first order elimination kinetics. Based on this, model -independent non-compartmental analysis (NCA) was used to determine the IVT ti / 2 (observed decay rate represents a true elimination ti / 2). Body components were not taken into consideration. Results are shown for rabbit FIG. 10A- 10B and in the top row of Table 15.

[0371] The NCA, 1C, and 3C models accurately represented the vitreous humor concentrations from the rabbit study (FIG. 10A-10B). The NCA ti / 2 of 5.1 days confirmed the 1C model ti / 2 of 5.3 days and the 3C model ti / 2 of 5 days. These values also confirmedother IgGs used in IVT injection. Taken together, these results supported the use of the 1C model to predict and scale the 11 / 2 for rat and human.

[0372] The rabbit PK parameters and IVT dose scaling from efficacious doses in the rat LCNV model were used to inform human dosing. Key parameters are shown in Table 15. The ti / 2 ranged from 0.34 days in the rat, with a vitreous volume of 50 pL, to 9.6 days in the human with a vitreous volume of 4 mL. Results are shown for a single efficacious 50 pg / eye ADI-60143 LALA dose via IVT injection in rat, which corresponded to 141 pg / eye in humans. The larger vitreous humor volume and longer 11 / 2 in humans balanced each other. Single ADI-60143 LALA IVT injections of 8 and 16 pg / eye were also effective in the rat LCNV model, and corresponded to 23 and 45 pg / eye in humans, respectively. The highest planned human dose of 10.0 mg / eye exceeded these values by greater than 10-fold.Table 15. Intravitreal Dose Scaling: Animal to Human5’Abbreviatoins: 1C = one-compartment;3C = three-compartment;AUC = area under the drug concentration versus time curve;AUC = area under the curve at steady-state;CL = clearance; d = day(s);NCA = non-compartmental analysis; ti / 2 = half-life;VH = vitreous humor; andVol. = volume.aNCA 1C model using a-single injection of ADI-60143 LALA IVT efficacious dose in rat (50 mg / eye)bNCA validated using rabbit data.

[0373] The 3C model successfully determined aqueous humor, retina, and choroid / RPE concentrations in the rabbit (FIG. 11). Retina and choroid / RPE were at equilibrium and had a partition coefficient of 1. The concentration in these regions was about 20-fold lower than the vitreous concentration.

[0374] The 3C model was used to determine human compartment concentrations of over time for ADI-60143 LALA concentrations at steady-state with IVT dosing Q4W. Results are present in nM concentration units in FIG. 11. The site of ADI-60143 LALA action is fibrin deposits in the retina and choroid / RPE. To be effective, the drug should be present at a concentration greater than the KD, which was approximately 1 nM for ADI-60143 LALA. For 10 mg IVT Q4W, which corresponded to a 100 pL injection, the ADI-60143 LALA retina / RPE concentration was greater than 10-fold the KD (~10 nM) for 71 days (Table 16). For 5 and 2.5 mg / eye dosing, the retina / RPE concentration was greater than 10 nM for 60 and 49 days, respectively (Table 16). This determined that ADI-60143 LALA was effective, with retina and choroid / RPE concentrations >10 nM, at all dose ranges used in the DME clinical trial (1.2-10 mg / eye Q4W) described in Example 10. Further, this identified that ADI-60143 LALA was effective at dosing intervals that are longer than Q4W, such as 10 mg / eye every two months.Table 16. Estimated Effective Drug Duration Time at Steady StateIVT = intravitreal; Q4W = every 4 weeksDrug product is 100 mg / mL, corresponding injections could 25, 50 and 100 pL, or the product could be dilutedExample 8: A Phase la Study of the Safety and Biological Activity of Intravitreal ADI-60143 LALA in Healthy Subjects

[0375] ADI-60143 LALA was evaluated in a randomized, double-blind, placebo- controlled trial to assess the safety, tolerability, and PK of single and multiple ascendingdoses (SAD and MAD) in healthy subjects. The SAD portion included 6 cohorts with 8 participants each (n=6 ADI-60143 LAL A and n=2 placebo) receiving IV doses ranging from 0.3 to 40.0 mg / kg. MAD participants received 3 doses, initially Q2W at 3.0 mg / kg and 10 mg / kg, then Q4W at 20 mg / kg and 40 mg / kg. Safety assessments included rotational thromboelastometry (ROTEM) to evaluate any impact on coagulation and fibrinolysis.

[0376] ADI-60143 was safe and well-tolerated at all doses with only 6 adverse events which were mild, related to the infusion site and resolved without sequelae. There were no clinically significant changes observed in lab results, vital signs, or ECG. ADI-60143 had no impact on coagulation and fibrinolysis, as measured by PT, aPTT and ROTEM. Population PK determinations suggested that ADI-60143 LAL A exhibited dose proportional pharmacokinetics and a terminal half-life of 38 days, supporting monthly or less frequent dosing. Taken together, these results demonstrated that ADI-60143 LALA was safe and well tolerated in healthy subjects following intravenous injection of single and multiple ascending doses up to 40 mg / kg in a Phase la study.Example 9: An Open-Label, Randomized, Controlled Phase l / 2a, Study of the Safety and Biological Activity of Intravitreal ADI-60143 LALA in Nonproliferative Diabetic Retinopathy and Diabetic Macular Edema

[0377] Described herein is a Phase l / 2a study to evaluate the safety, tolerability, and biologic activity of ADI-60143 LALA after single and multiple doses, administered by intravitreal injection (IVT or IVIT, used interchangeably herein), in a population of individuals with non-proliferative diabetic retinopathy (DR) and center-involving diabetic macular edema (DME). The study schema is shown in FIG 8.

[0378] This study consists of 2 phases: a SAD phase (Phase 1), and a randomized, standard-of-care (SOC) controlled phase of repeat monthly IVT dosing of the maximum tolerated dose (MTD) from Phase 1 in individuals with non-proliferative DR and centerinvolving DME who were previously treated (Phase 2a, Part A) or are treatment naive (Phase 2a, Part B). Each individual participates in only 1 cohort during the study.

[0379] The primary objectives are to assess the safety and tolerability of single ascending doses (SAD) of IVT ADI-60143 LALA in individuals with non-proliferative DR and centerinvolving DME (Phase 1 and 2) and to assess the safety and tolerability of repeated monthly doses of IVT ADI-60143 LALA in individuals with non-proliferative DR and centerinvolving DME (Phase 2a).

[0380] The secondary objectives are to assess the clinical activity of monthly IVT ADI- 60143 LALA in comparison to standard-of-care (SOC) IVT anti-VEGF therapy (e.g., aflibercept, Eylea) in individuals with non-proliferative DR and center-involving DME who were previously treated (Phase 2a, Part A) or are treatment naive (Phase 2a, Part B).SAD Phase 1

[0381] Phase 1 is an open-label, sequentially enrolled, non-controlled, SAD study in 3 cohorts of male and female individuals with non-proliferative DR and center-involving DME who have been previously treated. Informed consent is obtained from all individuals before any study -related procedures are conducted. Following screening, assessments (up to 21 days) are made to determine eligibility for participation in the study. Individuals are enrolled and a study eye is designated to receive a single dose of ADI-60143 LALA (study treatment). Prior to study treatment, baseline clinical (vital signs, ophthalmologic examinations, ocular imaging) and clinical laboratory (clinical chemistry, hematology, coagulation, and urinalysis) based safety evaluations are obtained, as well as aqueous humor sampling from the study eye’s anterior chamber for biomarkers and pharmacokinetics (PK). Study treatment is administered IVT to the study eye. Individuals undergo multiple clinical and laboratory -based safety related assessments, as well as aqueous humor sampling for biomarkers and PK at multiple time-points per the Schedule of Events (Table 17).

[0382] The following treatments are administered:Table 17: SAD Dosing Regimen

[0383] The starting dose is selected with consideration of various methods related to pharmacologically active dose (PAD), minimum anticipated biological effect level (MABEL) and no observed adverse effect level (NOAEL) as recommended by European Medicines Agency (EMA) and Food and Drug Administration (FDA) guidance. Toxicological assessments of ADI-60143 LALA from rodents and primates are used to determine the safety margins.

[0384] In this study, individuals are dosed according to a sentinel dosing design to ensure optimal safety. This means that initially 1 individual is dosed with ADI-60143 LALA. When the safety and tolerability results are observed and are acceptable to the Investigator at one week following dosing for the sentinel individuals, the other individuals within the cohort are dosed.

[0385] Advancement of cohorts is guided by prespecified criteria. After all three cohorts are dosed, a data safety monitoring committee (DSMC) reviews all available data to make a determination of MTD, the dose to be used in Phase 2a.Phase 2a

[0386] Phase 2a is an open-label, randomized, controlled, study of monthly repeat dosing in male and female individuals with non-proliferative DR and center-involving DME who have been previously treated (Part A) or are treatment naive (Part B). After informed consent is obtained and screening assessments to determine eligibility are performed, eligible individuals are enrolled and a study eye is designated. Individuals are randomized (2: 1) to receive repeat monthly dosing for 3 months of ADI-60143 LALA (study treatment) or standard-of-care anti-VEGF therapy (aflibercept, Eylea 2mg). Baseline and study assessments are the same as Phase 1. For individuals randomized to receive ADI-60143 LALA, specified criteria are used to identify the need for rescue with SOC anti-VEGF therapy.Study EndpointsPrimary Endpoint

[0387] Evaluation of safety and tolerability through ophthalmic exam and adverse events are used.Secondary Endpoints

[0388] Changes in Best Corrected Visual Acuity (BCVA), as well as changes in Central Retinal Thickness by spectral domain optical coherence tomography (SD-OCT) are used. Exploratory Endpoints:

[0389] Changes in levels of inflammatory biomarkers in aqueous humor, as available, are used. Changes in retinal anatomy on wide-field color fundus photography, wide-field fluoresceine angiography (FA), and optical coherence tomography - angiography (OCT- A), are used.Pharmacokinetics and Product Metabolism in Humans

[0390] Following dosing in healthy subjects of the SAD cohorts (2.5 mg / eye, 5 mg / eye, and 7.5 mg / eye), PK data are analyzed, as available.Safety and Efficacy

[0391] Study treatment-related AEs are observed, though AEs are mild in severity, related to the injection site, and require no further action or additional treatment.

[0392] Overall, intravitreal treatment with ADI-60143 LALA in healthy subjects is well tolerated.Example 10: An Open-Label Phase 1 Study of the Safety and Biological Activity of Intravitreal ADI-60143 LALA in Diabetic Macular Edema

[0393] Described herein is a Phase 1 study to evaluate the safety, tolerability, and biologic activity of ADI-60143 LALA after multiple doses, administered by intravitreal injection (IVT) in a population of individuals with diabetic macular edema (DME). The study schema is shown in FIG 9.Study Design

[0394] The Phase 1 study is an open-label, non-controlled, multiple ascending dose (MAD) study that enrolls treatment-experienced participants with DME secondary to nonproliferative diabetic retinopathy (NPDR).

[0395] The primary objectives assess the safety and tolerability of ADI-60143 LALA administered by IVT injection every 4 weeks for a total of 3 doses. The secondary objectives evaluate the effect of IVT ADI-60143 LALA on restoring Best Corrected Visual Acuity (BCVA) and retinal anatomy as measured by spectral domain optical coherence tomography (OCT), as well as fluorescein angiography (FA) and wide-field color fundus photographs. Exploratory evaluations include OCT Angiography (OCTA), the effect of IVT ADI-60143 LALA on inflammatory biomarkers and macular macrophage-like cell density. Up to 21 participants are enrolled initially into 3 sequential cohorts (3, 9, and 9 participants in Cohorts 1, 2, and 3, respectively) to receive ADI-60143 LALA by IVT injection every 4 weeks for a total of 3 doses.

[0396] Cohort 1 enrolls DME treatment-experienced participants only and Cohorts 2 and 3 enroll DME treatment-experienced and DME treatment-naive participants, respectively, with a minimum of 5 treatment-naive participants in each of Cohorts 2 and 3. Additionally, enrolled subjects have BVCA between 70 and 35 letters (inclusive), using Early TreatmentDiabetic Retinopathy Study (ETDRS) testing (e.g., about 20 / 40 to 20 / 200 (inclusive) by Snellen chart). Enrolled subjects also have central subfield thickness of > 325 pM.

[0397] While the disclosure has been particularly shown and described with reference to a preferred embodiment and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the spirit and scope of the disclosure.

[0398] All references, issued patents and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes.INFORMAL SEQUENCE LISTINGIll

Claims

CLAIMS1. A dosage form comprising an isolated antibody that binds human fibrin yC or fibrinogen yC domain, wherein the dosage form comprises the isolated antibody at a concentration of from 20 mg / mL to 200 mg / mL, and wherein the isolated antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein, respectively: a. CDR-H1 comprises the sequence set forth in SEQ ID NOs: 157, 1, 13, 25, 37,49, 61, 73, 85, 97, 109, 121, 133, 145, 169, 181, 193, 205, 217, or 229; b. CDR-H2 comprises the sequence set forth in SEQ ID NOs: 158, 2, 14, 26, 38,50, 62, 74, 86, 98, 110, 122, 134, 146, 170, 182, 194, 206, 218, or 230; c. CDR-H3 comprises the sequence set forth in SEQ ID NOs: 159, 3, 15, 27, 39,51, 63, 75, 87, 99, 111, 123, 135, 147, 171, 183, 195, 207, 219, or 231; d. CDR-L1 comprises the sequence set forth in SEQ ID NOs: 160, 4, 16, 28, 40,52, 64, 76, 88, 100, 112, 124, 136, 148, 172, 184, 196, 208, 220, or 232; e. CDR-L2 comprises the sequence set forth in SEQ ID NOs: 161, 5, 17, 29, 41,53, 65, 77, 89, 101, 113, 125, 137, 149, 173, 185, 197, 209, 221, or 233; and f. CDR-L3 comprises the sequence set forth in SEQ ID NOs: 162, 6, 18, 30, 42,54, 66, 78, 90, 102, 114, 126, 138, 150, 174, 186, 198, 210, 222, or 234.

2. The dosage form of claim 1, wherein the isolated antibody comprises a VH sequence selected from a sequence set forth in any one of SEQ ID NOs: 163, 7, 19, 31, 43, 55, 67, 79, 91, 103, 115, 127, 139, 151, 175, 187, 199, 211, 223, or 235.

3. The dosage form of claim 1 or 2, wherein the isolated antibody comprises a VL sequence selected from a sequence set forth in SEQ ID NOs: 166, 10, 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154, 178, 190, 202, 214, 226, or 238.

4. The dosage form of any one of claims 1-3, wherein the isolated antibody comprises a VH sequence set forth in SEQ ID NO: 163 and a VL sequence set forth in SEQ ID NO: 166.The dosage form of any one of claims 1-3, wherein the isolated antibody comprises:(a) a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 10;(b) a VH sequence set forth in SEQ ID NO: 19 and a VL sequence set forth in SEQ ID NO: 22;(c) a VH sequence set forth in SEQ ID NO: 31 and a VL sequence set forth in SEQ ID NO: 34;(d) a VH sequence set forth in SEQ ID NO: 43 and a VL sequence set forth in SEQ ID NO: 46;(e) a VH sequence set forth in SEQ ID NO: 55 and a VL sequence set forth in SEQ ID NO: 58;(f) a VH sequence set forth in SEQ ID NO: 67 and a VL sequence set forth in SEQ ID NO: 70;(g) a VH sequence set forth in SEQ ID NO: 79 and a VL sequence set forth in SEQ ID NO: 82;(h) a VH sequence set forth in SEQ ID NO: 91 and a VL sequence set forth in SEQ ID NO: 94;(i) a VH sequence set forth in SEQ ID NO: 103 and a VL sequence set forth in SEQ ID NO: 106;(j) a VH sequence set forth in SEQ ID NO: 115 and a VL sequence set forth in SEQ ID NO: 118;(k) a VH sequence set forth in SEQ ID NO: 127 and a VL sequence set forth in SEQ ID NO: 130;(l) a VH sequence set forth in SEQ ID NO: 139 and a VL sequence set forth in SEQ ID NO: 142;(m)a VH sequence set forth in SEQ ID NO: 151 and a VL sequence set forth in SEQ ID NO: 154;(n) a VH sequence set forth in SEQ ID NO: 175 and a VL sequence set forth in SEQ ID NO: 178;(o) a VH sequence set forth in SEQ ID NO: 187 and a VL sequence set forth in SEQ ID NO: 190;(p) a VH sequence set forth in SEQ ID NO: 199 and a VL sequence set forth in SEQ ID NO: 202;(q) a VH sequence set forth in SEQ ID NO: 211 and a VL sequence set forth in SEQ ID NO: 214;(r) a VH sequence set forth in SEQ ID NO: 223 and a VL sequence set forth in SEQ ID NO: 226;(s) a VH sequence set forth in SEQ ID NO: 235 and a VL sequence set forth in SEQ ID NO: 238; or(t) a VH sequence set forth in SEQ ID NO: 256 and a VL sequence set forth in SEQ ID NO: 257.

6. The dosage form of any one of claims 1-5, wherein the isolated antibody comprises a humanized, human, or chimeric antigen binding region.

7. The dosage form of claim 6, wherein the isolated antibody comprises a humanized antibody or antigen binding region.

8. The dosage form of any one of claims 1-7, wherein the isolated antibody comprises a heavy chain human Fc region of a class selected from IgG, IgA, IgD, IgE, and IgM.

9. The dosage form of claim 8, wherein the human Fc region comprises a human heavy chain constant region of the class IgG and a subclass selected from IgGl, IgG2, IgG3, and IgG4.

10. The dosage form of claim 9, wherein the human Fc region comprises wild-type, human IgGl Fc.

11. The dosage form of claim 9, wherein the human Fc domain comprises a sequence set forth in SEQ ID NOs: 164, 8, 20, 32, 44, 56, 68, 80, 92, 104, 116, 128, 140, 152, 176, 188, 200, 212, 224, or 236.

12. The dosage form of any one of claims 1-11, wherein the heavy chain comprises a constant heavy chain sequence set forth by SEQ ID NOs: 164, 8, 20, 32, 44, 56, 68, 80, 92, 104, 116, 128, 140, 152, 176, 188, 200, 212, 224, or 236.

13. The dosage form of any one of claims 1-12, wherein the light chain comprises a constant light chain sequence set forth by SEQ ID NOs: 165, 9, 21, 33, 45, 57, 69, 81, 93, 105, 117, 129, 141, 153, 177, 189, 201, 213, 225, or 237.

14. The dosage form of any one of claims 8-13, wherein the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions result inincreased half-life, reduced or increased FcyR binding, reduced or increased Clq binding, reduced or increased FcRn binding, reduced or increased ADCC activity, reduced or increased ADCP activity, or reduced or increased CDC activity compared with the Fc without the one or more substitutions.

15. The dosage form of any one of claims 8-14, wherein the Fc region binds an Fey Receptor selected from the group consisting of: FcyRI, FcyRIIa, FcyRIIb, FcyRIIc, FcyRIIIa, and FcyRIIIb.

16. The dosage form of any one of claims 1-15, wherein the isolated antibody comprises a monoclonal antigen binding region.

17. The dosage form of any one of claims 1-16, wherein the isolated antibody binds an y377-395 epitope of the fibrin yC or fibrinogen yC domain.

18. The dosage form of any one of claims 1-17, wherein the isolated antibody binds to peptide comprising an amino acid sequence set forth in at least one of SEQ ID NOs: 241, and 249-253 with a KD of less than or equal to 1, 2, 3, 4, 5, 6, 7, or 8 x 10'7to 10’ 9 nM, as measured by a surface plasmon resonance (SPR), single cycle kinetics (SCK), or biolayer interferometry assay.

19. The dosage form of any one of claims 1-18, wherein the isolated antibody binds to a peptide comprising the sequence of the y377 -395 epitope of the human fibrin yC or fibrinogen yC domain with a KD of less than or equal to 10'7to 10'9nM, as measured by an SPR, SCK, or biolayer interferometry assay, optionally wherein the y377 -395 epitope of the human fibrin yC or fibrinogen yC domain comprises the sequence of SEQ ID NO: 241.

20. The dosage form of any one of claims 1-19, wherein the isolated antibody inhibits CD1 lb / CD18 (Mac-1) and CD1 lc / CD18 binding to fibrin yC or fibrinogen yC domain, optionally measured by a competition assay, ELISA assay, or flow cytometry.

21. The dosage form of any one of claims 1-20, wherein the isolated antibody exhibits inhibition of microglial and / or macrophage adhesion to the fibrin yC or fibrinogen yC domain, optionally measured by a competition assay, ELISA assay, or flow cytometry.

22. The dosage form of any one of claims 1-21, wherein the isolated antibody binds human fibrin at any one of amino acid residues Lys 411, He 412, He 413, Phe 415, Asn 416, Arg 417, Leu 418, Thr 419, lie 420, and Gly 421 relative to SEQ ID NO: 265, optionally measured by alanine scanning, X-ray crystallography, a peptide array, hydrogen-deuterium exchange, cryo-electron microscopy, or antibody binding epitope mapping.

23. The dosage form of claim 22, wherein the isolated antibody binds human fibrin at least two, three, four, five, six, seven, eight, nine, or all ten of amino acid residues Lys 411, lie 412, lie 413, Phe 415, Asn 416, Arg 417, Leu 418, Thr 419, lie 420, and Gly 421 relative to SEQ ID NO: 265, optionally measured by alanine scanning, X-ray crystallography, a peptide array, hydrogen-deuterium exchange, cryo-electron microscopy, or antibody binding epitope mapping.

24. The dosage form of any one of claims 1-23, wherein the dosage form is formulated for local (e.g., intravitreal, subconjunctival, retrobulbar, and intracameral), topical, or systemic administration.

25. The dosage form of claim 24, wherein the dosage form is formulated for intravitreal administration.

26. The dosage form of any one of claims 1-25, wherein the dosage form comprises the isolated antibody at a concentration of greater than 40, 60, 80, 100, 120, 160, 180, or 200 mg / mL.

27. The dosage form of any one of claims 1-25, wherein the dosage form comprises the isolated antibody at a concentration of 100 mg / mL.

28. A method of treating a disorder or condition of the eye in a subject in need thereof, the method comprising administering to the subject the dosage form of any one of claims 1-27.

29. The dosage form of any one of claims 1-27 for use in the treatment of a disorder or condition of the eye in a subject in need thereof.

30. A method of treating a disorder or condition of the eye in a subject in need thereof, the method comprising administering to the subject one or more doses of a dosage form comprising an isolated antibody that binds human fibrin yC or fibrinogen yCdomain, each dose selected from 1 mg to 20 mg to each eye of the isolated antibody, wherein the isolated antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR- H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein, respectively: a. CDR-H1 comprises the sequence set forth in SEQ ID NOs: 157, 1, 13, 25, 37,49, 61, 73, 85, 97, 109, 121, 133, 145, 169, 181, 193, 205, 217, or 229; b. CDR-H2 comprises the sequence set forth in SEQ ID NOs: 158, 2, 14, 26, 38,50, 62, 74, 86, 98, 110, 122, 134, 146, 170, 182, 194, 206, 218, or 230; c. CDR-H3 comprises the sequence set forth in SEQ ID NOs: 159, 3, 15, 27, 39,51, 63, 75, 87, 99, 111, 123, 135, 147, 171, 183, 195, 207, 219, or 231; d. CDR-L1 comprises the sequence set forth in SEQ ID NOs: 160, 4, 16, 28, 40,52, 64, 76, 88, 100, 112, 124, 136, 148, 172, 184, 196, 208, 220, or 232; e. CDR-L2 comprises the sequence set forth in SEQ ID NOs: 161, 5, 17, 29, 41,53, 65, 77, 89, 101, 113, 125, 137, 149, 173, 185, 197, 209, 221, or 233; and f. CDR-L3 comprises the sequence set forth in SEQ ID NOs: 162, 6, 18, 30, 42,54, 66, 78, 90, 102, 114, 126, 138, 150, 174, 186, 198, 210, 222, or 234.

31. A method of treating a disorder or condition of the eye in a subject in need thereof, the method comprising administering to the subject one or more doses of a dosage form comprising a means for binding human fibrin yC or fibrinogen yC domain, each dose selected from 1 mg to 20 mg to each eye of the means for binding human fibrin yC or fibrinogen yC domain.

32. The method of claim 30 or 31, wherein the dosage form is administered to the subject in one or more doses, each dose selected from 1 mg to 20 mg to each eye.

33. The method of any one of claims 30-32, wherein each dose is selected from 1 mg, 1.2 mg, 2.5 mg, 3.5 mg, 5 mg, 7.5 mg, 10 mg, 12 mg, and 15 mg to each eye of the isolated antibody.

34. The method of any one of claims 30, 32, or 33, wherein each dose is 2.5 mg to each eye of the isolated antibody.

35. The method of any one of claims 30, 32, or 33, wherein each dose is 5 mg to each eye of the isolated antibody.

36. The method of any one of claims 30, 32, or 33, wherein each dose is 7.5 mg to each eye of the isolated antibody.

37. The method of any one of claims 30, 32, or 33, wherein each dose is 10 mg to each eye of the isolated antibody.

38. The method of any one of claims 30, 32, or 33, wherein each dose is 12 mg to each eye of the isolated antibody.

39. The method of any one of claims 30, 32, or 33, wherein each dose is 15 mg to each eye of the isolated antibody.

40. The method of any one of claims 28-30 and 32-39, wherein the dosage form comprises the isolated antibody at a concentration of from 20 mg / mL to 200 mg / mL.

41. The dosage form of any one of claims 28-30 and 32-40, wherein the dosage form comprises the isolated antibody at a concentration of greater than 40, 60, 80, 100, 120, 160, 180, or 200 mg / mL.

42. The dosage form of any one of claims 28-30 and 32-40, wherein the dosage form comprises the isolated antibody at a concentration of 100 mg / mL.

43. The method of any one of claims 28-42, wherein the method comprises administering the dosage form to the subject one time per month, once every six weeks, or once every two or once every three months for one or more months.

44. The method of claim 43, wherein the method comprises administering the dosage form to the subject one time per month.

45. The method of claim 43, wherein the method comprises administering the dosage form to the subject one time per two months.

46. The method of claim 43, wherein the method comprises administering the dosage form to the subject one time per three months.

47. The method of any one of claims 43-46, wherein the method comprises administering the dosage form to the subject three or more times.

48. The method of any one of claims 28-30 and 32-47, wherein the isolated antibody is administered to the subject at the same dose at each administration.

49. The method of any one of claims 28-48, wherein the method comprises administering the dosage form locally (e.g., intravitreally, subconjunctivally, retrobulbarly, and intracamerally), topically, and systemically.

50. The method of claim 49, wherein the method comprises administering the dosage form intravitreally.

51. The method of any one of claims 28-50, further comprising administering to the subject an effective amount of one or more anti -vascular endothelial growth factor (VEGF) antibodies or antigen-binding fragments thereof.

52. The method of claim 51, wherein the anti -VEGF antibodies or antigen-binding fragments thereof comprise aflibercept, ranibizumab, bevacizumab efdamrofusp alfa, and faricimab-svoa and biosimilars thereof.

53. The method of claim 52, wherein the anti -VEGF antibody or antigen-binding fragment thereof is aflibercept.

54. The method of claim 52, wherein the anti-VEGF antibody or antigen-binding fragment thereof is bevacizumab.

55. The method of any one of claims 28-54, wherein the disorder or condition of the eye comprises retinitis pigmentosa, age-related macular degeneration, glaucoma, diabetic retinopathy, diabetic macular edema, uveitis, and retinal detachment.

56. The method of claim 55, wherein the disorder or condition of the eye is diabetic macular edema.

57. The method of any one of claims 28-56, wherein the subject is a human.

58. A dosage form comprising an isolated antibody that binds human fibrin yC or fibrinogen yC domain for use in the treatment of a disorder or condition of the eye in a subject in need thereof, the use comprising administering to the subject one or more doses of the dosage form, each dose selected from 1 mg to 20 mg to each eye of the isolated antibody, wherein the isolated antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light (VL)chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, andCDR-L3, wherein, respectively: a. CDR-H1 comprises the sequence set forth in SEQ ID NOs: 157, 1, 13, 25, 37,49, 61, 73, 85, 97, 109, 121, 133, 145, 169, 181, 193, 205, 217, or 229; b. CDR-H2 comprises the sequence set forth in SEQ ID NOs: 158, 2, 14, 26, 38,50, 62, 74, 86, 98, 110, 122, 134, 146, 170, 182, 194, 206, 218, or 230; c. CDR-H3 comprises the sequence set forth in SEQ ID NOs: 159, 3, 15, 27, 39,51, 63, 75, 87, 99, 111, 123, 135, 147, 171, 183, 195, 207, 219, or 231; d. CDR-L1 comprises the sequence set forth in SEQ ID NOs: 160, 4, 16, 28, 40,52, 64, 76, 88, 100, 112, 124, 136, 148, 172, 184, 196, 208, 220, or 232; e. CDR-L2 comprises the sequence set forth in SEQ ID NOs: 161, 5, 17, 29, 41,53, 65, 77, 89, 101, 113, 125, 137, 149, 173, 185, 197, 209, 221, or 233; and f. CDR-L3 comprises the sequence set forth in SEQ ID NOs: 162, 6, 18, 30, 42,54, 66, 78, 90, 102, 114, 126, 138, 150, 174, 186, 198, 210, 222, or 234.

59. A method of treating diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the method comprising intravitreally administering to the subject a dosage form comprising an isolated antibody that binds human fibrin yC or fibrinogen yC domain, wherein the dosage form comprises the isolated antibody at a concentration of 100 mg / mL, and wherein the isolated antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein, respectively: a. CDR-H1 comprises the sequence set forth in SEQ ID NO: 157; b. CDR-H2 comprises the sequence set forth in SEQ ID NOs: 158; c. CDR-H3 comprises the sequence set forth in SEQ ID NOs: 159; d. CDR-L1 comprises the sequence set forth in SEQ ID NOs: 160; e. CDR-L2 comprises the sequence set forth in SEQ ID NOs: 161; and f. CDR-L3 comprises the sequence set forth in SEQ ID NOs: 162.

60. A method of treating diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the method comprising intravitreally administering to the subject a dosage form comprising a means for binding human fibrin yC or fibrinogen yC domain, wherein the dosage form comprises the means for binding human fibrin yC or fibrinogen yC domain at a concentration of 100 mg / mL.

61. The method of claim 59 or 60, wherein the method comprises administering the dosage form to the subject one, two, three, or four times per month; or once every six or eight weeks for one or more months (e.g., three months).

62. The method of claim 59 or 60, wherein the method comprises administering the dosage form to the subject one time per month.

63. The method of any one of claims 59, 61, or 62, wherein the isolated antibody is administered to the subject at the same dose at each administration.

64. The method of any one of claims 59-63, wherein the method comprises administering the dosage form to the subject for three or more months.

65. The method of claim 64, wherein the method comprises administering the dosage form to the subject for three months.

66. A method of treating diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the method comprising intravitreally administering to the subject one or more doses of a dosage form comprising an isolated antibody that binds human fibrin yC or fibrinogen yC domain, each dose selected from 1.2 mg, 3.5 mg, and 10 mg to each eye of the isolated antibody, wherein the isolated antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein, respectively: a. CDR-H1 comprises the sequence set forth in SEQ ID NO: 157; b. CDR-H2 comprises the sequence set forth in SEQ ID NOs: 158; c. CDR-H3 comprises the sequence set forth in SEQ ID NOs: 159; d. CDR-L1 comprises the sequence set forth in SEQ ID NOs: 160; e. CDR-L2 comprises the sequence set forth in SEQ ID NOs: 161; andf. CDR-L3 comprises the sequence set forth in SEQ ID NOs: 162.

67. A method of treating diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the method comprising intravitreally administering to the subject one or more doses of a dosage form comprising a means for binding human fibrin yC or fibrinogen yC domain, each dose selected from 1.2 mg, 3.5 mg, and 10 mg to each eye of the means for binding human fibrin yC or fibrinogen yC domain.

68. The method of claim 66 or 67, wherein the method comprises administering the dosage form to the subject one, two, three, or four times per month; or once every six or eight weeks for one or more months (e.g., three months).

69. The method of claim 68, wherein the method comprises administering the dosage form to the subject one time per month.

70. The method of any one of claims 66, 68, or 69, wherein the isolated antibody is administered to the subject at the same dose at each administration.

71. The method of any one of claims 66-70, wherein the method comprises administering the dosage form to the subject for three or more months.

72. The method of claim 71, wherein the method comprises administering the dosage form to the subject for three months.

73. A dosage form comprising an isolated antibody that binds human fibrin yC or fibrinogen yC domain for use in the treatment of diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the use comprising intravitreally administering to the subject the dosage form, wherein the dosage form comprises the isolated antibody at a concentration of 100 mg / mL, and wherein the isolated antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein, respectively: a. CDR-H1 comprises the sequence set forth in SEQ ID NO: 157; b. CDR-H2 comprises the sequence set forth in SEQ ID NOs: 158; c. CDR-H3 comprises the sequence set forth in SEQ ID NOs: 159; d. CDR-L1 comprises the sequence set forth in SEQ ID NOs: 160;e. CDR-L2 comprises the sequence set forth in SEQ ID NOs: 161; and f. CDR-L3 comprises the sequence set forth in SEQ ID NOs: 162.

74. A dosage form comprising an isolated antibody that binds human fibrin yC or fibrinogen yC domain for use in the treatment of diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the use comprising intravitreally administering to the subject one or more doses of the dosage form, each dose selected from 1.2 mg, 3.5 mg, and 10 mg to each eye of the isolated antibody, wherein the isolated antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein, respectively: a. CDR-H1 comprises the sequence set forth in SEQ ID NO: 157; b. CDR-H2 comprises the sequence set forth in SEQ ID NOs: 158; c. CDR-H3 comprises the sequence set forth in SEQ ID NOs: 159; d. CDR-L1 comprises the sequence set forth in SEQ ID NOs: 160; e. CDR-L2 comprises the sequence set forth in SEQ ID NOs: 161; and f. CDR-L3 comprises the sequence set forth in SEQ ID NOs: 162.

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