ANTI-BETACELLULIN ANTIBODIES, FRAGMENTS THEREOF, AND MULTI-SPECIFIC BINDING MOLECULES
The present disclosure provides anti-BTC antibodies, methods of producing said antibodies, pharmaceutical compositions comprising said antibodies, and methods of using said antibodies. The present disclosure also provides multi-specific binding molecules, e.g., bispecific antibodies, comprising a BTC binding moiety and an anti-VEGF binding moiety.
1 - 35 . (canceled)
36 . A multi-specific binding molecule comprising 1) an anti-betacellulin (BTC) binding moiety and 2) an anti-vascular endothelial growth factor (VEGF) binding moiety.
37 . The multi-specific binding molecule of claim 36 , which blocks BTC binding to ErbB1, ErbB4, or both.
38 . The multi-specific binding molecule of claim 36 , which blocks BTC-induced phospoh-ERK1/2 activation.
39 . The multi-specific binding molecule of claim 36 , which blocks BTC-induced phospoh-HER3 activation.
40 . The multi-specific binding molecule of claim 36 , wherein the anti-BTC binding moiety is an anti-BTC antibody or antigen binding fragment thereof in a format selected from the group consisting of an isolated antibody, a Fab, a Fab′, a F(ab′) 2 , a Fv, and a scFv.
41 . The multi-specific binding molecule of claim 40 , wherein the anti-BTC binding moiety is an anti-BTC Fab comprising a heavy chain (HA) and a light chain (LA).
42 . The multi-specific binding molecule of claim 41 , wherein the anti-BTC Fab comprises an Fc region selected from a group consisting of IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE, and IgD.
43 . The multi-specific binding molecule of claim 41 , wherein the anti-VEGF binding moiety is an anti-VEGF antibody or antigen binding fragment thereof in a format selected from the group consisting of an isolated antibody, a Fab, a Fab′, a F(ab′) 2 , a Fv, and a scFv.
44 . The multi-specific binding molecule of claim 43 , wherein the anti-VEGF binding moiety is brolucizumab, aflibercept, or a derivative thereof.
45 . The multi-specific binding molecule of claim 43 , wherein the anti-VEGF binding moiety is an anti-VEGF Fab comprising a heavy chain (HB) and a light chain (LB).
46 . The multi-specific binding molecule of claim 45 , wherein the HA and the HB are linked in the format from the N-terminus to the C-terminus: N-HA-linker 1-HB-C, and wherein the LA and the LB are linked in the format from the N-terminus to the C-terminus: N-LA-linker 2-LB-C.
47 . A polynucleotide comprising a nucleotide sequence encoding the multi-specific binding molecule of claim 36 .
48 . An expression cassette or a vector comprising the polynucleotide of claim 47 .
49 . A host cell comprising the expression cassette or vector of claim 48 .
50 . A pharmaceutical composition comprising an effective amount of the multi-specific binding molecule of claim 36 .
51 . A method of treating an ophthalmic disorder in a subject in need thereof, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 50 , wherein the ophthalmic disorder is selected from the group consisting of diabetic macular edema, age-related macular degeneration, neovascular age-related macular degeneration, neovascular glaucoma, diabetic retinopathy, macular edema, pathologic myopia, retinal vein occlusions, retinopathy of prematurity, and abnormal vascular proliferation associated with phakomatoses.
52 . The method of claim 51 , wherein the ophthalmic disorder is selected from the group consisting of macular edema, diabetic macular edema, neovascular age-related macular degeneration, and retinal vein occlusions.
53 . The method of claim 52 , further comprising administering intravitreally to the subject the multi-specific binding molecule at a dose about 0.25 mg/eye, 0.75 mg/eye, 2.5 mg/eye, or 7.5 mg/eye.
54 . A method of improving vision or visual acuity in a subject in need thereof, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 50 , wherein the subject has an ophthalmic disorder selected from the group consisting of diabetic macular edema, age-related macular degeneration, neovascular age-related macular degeneration, neovascular glaucoma, diabetic retinopathy, macular edema, pathologic myopia, retinal vein occlusions, retinopathy of prematurity, and abnormal vascular proliferation associated with phakomatoses.
55 . A kit comprising the multi-specific binding molecule of claim 36 .