An isolated antibody or fragment thereof that recognizes a conformational epitope of a Notch 3 receptor, wherein the conformational epitope comprises continuous and discontinuous amino acid sequences within a Lin Notch Repeat region, a heterodimerization domain of the negative regulatory region domain of Notch 3 receptor, and a linker region; wherein the LNR region is selected from the group consisting of LNR-A, LNR-B, and LNR-C; wherein the HD domain is selected from the group consisting of the N-terminal HD and the C-terminal HD; and wherein the antibody or fragment thereof blocks ligand-dependent signal transduction, wherein the antibody or fragment thereof stabilizes the Notch 3 receptor LNR region in the autoinhibited state, and wherein the antibody or fragment thereof comprises a heavy and light chain variable regions CDR1, CDR2 and CDR3 selected from the group consisting of a heavy chain variable region CDR1 of SEQ ID NO: 3; CDR2 of SEQ ID NO: 4; CDR3 of SEQ ID NO: 5 and a light chain variable region CDR1 of SEQ ID NO: 13; CDR2 of SEQ ID NO: 14; and CDR3 of SEQ ID NO: 15; or a heavy chain variable region CDR1 of SEQ ID NO: 23; CDR2 of SEQ ID NO: 24; CDR3 of SEQ ID NO: 25 and a light chain variable region CDR1 of SEQ ID NO: 33; CDR2 of SEQ ID NO: 34; and CDR3 of SEQ ID NO: 35; or a heavy chain variable region CDR1 of SEQ ID NO: 43; CDR2 of SEQ ID NO: 44; CDR3 of SEQ ID NO: 45 and a light chain variable region CDR1 of SEQ ID NO: 53; CDR2 of SEQ ID NO: 54; and CDR3 of SEQ ID NO: 55; or a heavy chain variable region CDR1 of SEQ ID NO: 63; CDR2 of SEQ ID NO: 64; CDR3 of SEQ ID NO: 65 and a light chain variable region CDR1 of SEQ ID NO: 73; CDR2 of SEQ ID NO: 74; and CDR3 of SEQ ID NO: 75; or a heavy chain variable region CDR1 of SEQ ID NO: 83; CDR2 of SEQ ID NO: 84; CDR3 of SEQ ID NO: 85 and a light chain variable region CDR1 of SEQ ID NO: 93; CDR2 of SEQ ID NO: 94; and CDR3 of SEQ ID NO: 95; or a heavy chain variable region CDR1 of SEQ ID NO: 103; CDR2 of SEQ ID NO: 104; CDR3 of SEQ ID NO: 105 and a light chain variable region CDR1 of SEQ ID NO: 113; CDR2 of SEQ ID NO: 114; and CDR3 of SEQ ID NO: 115; or a heavy chain variable region CDR1 of SEQ ID NO: 123; CDR2 of SEQ ID NO: 124; CDR3 of SEQ ID NO: 125 and a light chain variable region CDR1 of SEQ ID NO: 133; CDR2 of SEQ ID NO: 134; and CDR3 of SEQ ID NO: 135; or a heavy chain variable region CDR1 of SEQ ID NO: 143; CDR2 of SEQ ID NO: 144; CDR3 of SEQ ID NO: 145 and a light chain variable region CDR1 of SEQ ID NO: 153; CDR2 of SEQ ID NO: 154; and CDR3 of SEQ ID NO: 155; or a heavy chain variable region CDR1 of SEQ ID NO: 163; CDR2 of SEQ ID NO: 164; CDR3 of SEQ ID NO: 165 and a light chain variable region CDR1 of SEQ ID NO: 173; CDR2 of SEQ ID NO: 174; and CDR3 of SEQ ID NO: 175; or a heavy chain variable region CDR1 of SEQ ID NO: 183; CDR2 of SEQ ID NO: 184; CDR3 of SEQ ID NO: 185 and a light chain variable region CDR1 of SEQ ID NO: 193; CDR2 of SEQ ID NO: 194; and CDR3 of SEQ ID NO: 195; or a heavy chain variable region CDR1 of SEQ ID NO: 203; CDR2 of SEQ ID NO: 204; CDR3 of SEQ ID NO: 205 and a light chain variable region CDR1 of SEQ ID NO: 213; CDR2 of SEQ ID NO: 214; and CDR3 of SEQ ID NO: 215; or a heavy chain variable region CDR1 of SEQ ID NO: 223; CDR2 of SEQ ID NO: 224; CDR3 of SEQ ID NO: 225 and a light chain variable region CDR1 of SEQ ID NO: 233; CDR2 of SEQ ID NO: 234; and CDR3 of SEQ ID NO: 235.