Human Anti-OPGL Neutralizing Antibodies as Selective OPGL Pathway Inhibitors

An isolated human antibody that specifically binds osteoprotegerin ligand (OPGL), comprising a heavy chain and a light chain, wherein the light chain comprises a light chain variable region comprising an amino acid sequence as set forth in any of SEQ ID NO:

• 8, SEQ ID NO:
• 16, SEQ ID NO:
• 24, or SEQ ID NO:
• 28, or an antigen-binding or an immunologically functional immunoglobulin fragment thereof.

An isolated human antibody that specifically binds osteoprotegerin ligand (OPGL), comprising a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as set forth in any of SEQ ID NO:

• 30, SEQ ID NO:
• 38, SEQ ID NO:
• 46, or SEQ ID NO:
• 50, or an antigen-binding or an immunologically functional immunoglobulin fragment thereof.

An isolated human antibody that specifically binds osteoprotegerin ligand (OPGL), comprising a heavy chain and a light chain, wherein the light chain comprises an amino acid sequence as set forth in any of SEQ ID NO:

• 32, SEQ ID NO:
• 40, SEQ ID NO:
• 48, or SEQ ID NO:
• 52, or an antigen-binding or an immunologically functional immunoglobulin fragment thereof.

An isolated human antibody that specifically binds osteoprotegerin ligand (OPGL), wherein the antibody comprises:

• a. a heavy chain having a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO:
• 6, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain having a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO:
• 8, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof;
• b. a heavy chain having a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO:
• 14, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain having a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO:
• 16, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof;
• c. a heavy chain having a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO:
• 22, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain having a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO:
• 24, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof;
• d. a heavy chain having a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO:
• 26, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain having a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO:
• 28, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof;
• e. a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO:
• 30, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain comprising an amino acid sequence as set forth in SEQ ID NO:
• 32, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof;
• f. a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO:
• 38, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain comprising an amino acid sequence as set forth in SEQ ID NO:
• 40, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof;
• g. a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO:
• 46, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain comprising an amino acid sequence as set forth in SEQ ID NO:
• 48, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof;
• or
• h. a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO:
• 50, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain comprising an amino acid sequence as set forth in SEQ ID NO:
• 52, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof.

An isolated human antibody that specifically binds osteoprotegerin ligand (OPGL), wherein the antibody comprises:

• a. a heavy chain having a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO:
• 10, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain having a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO:
• 12, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof;
• b. a heavy chain having a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO:
• 18, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain having a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO:
• 20, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof;
• c. a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO:
• 34, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain comprising an amino acid sequence as set forth in SEQ ID NO:
• 36, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof;
• or
• d. a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO:
• 42, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain comprising an amino acid sequence as set forth in SEQ ID NO:
• 44, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof.

A heavy chain comprising a variable region and a constant region, wherein the variable region comprises an amino acid sequence as set forth in any of SEQ ID NO:

• 6, SEQ ID NO:
• 10, SEQ ID NO:
• 14, SEQ ID NO:
• 18, SEQ ID NO:
• 22, or SEQ ID NO:
• 26, or an antigen-binding or an immunologically functional immunoglobulin fragment thereof.

A heavy chain comprising an amino acid sequence as set forth in any of SEQ ID NO:

• 30, SEQ ID NO:
• 34, SEQ ID NO:
• 38, SEQ ID NO:
• 42, SEQ ID NO:
• 46, or SEQ ID NO:
• 50, or an antigen-binding or an immunologically functional immunoglobulin fragment thereof.

A light chain comprising a variable region and a constant region, wherein the variable region comprises an amino acid sequence as set forth in any of SEQ ID NO:

• 8, SEQ ID NO:
• 12, SEQ ID NO:
• 16, SEQ ID NO:
• 20, SEQ ID NO:
• 24, or SEQ ID NO:
• 28, or an antigen-binding or an immunologically functional immunoglobulin fragment thereof.

A light chain comprising an amino acid sequence as set forth in any of SEQ ID NO:

• 32, SEQ ID NO:
• 36, SEQ ID NO:
• 40, SEQ ID NO:
• 44, SEQ ID NO:
• 48, or SEQ ID NO:
• 52, or an antigen-binding or an immunologically functional immunoglobulin fragment thereof.

An isolated human antibody comprising:

• a. human heavy chain framework regions, a human heavy chain CDR1 region, a human heavy chain CDR2 region, and a human heavy chain CDR3 region, wherein the human heavy chain CDR3 region is the heavy chain CDR3 region of 16E1, 2D8, 22B3, or 9H7 as shown in FIG. 15;
• and
• b. human light chain framework regions, a human light chain CDR1 region, a human light chain CDR2 region, and a human light chain CDR3 region, wherein the human light chain CDR3 region is the light chain CDR3 region of 16E1, 2D8, 22B3, or 9H7 as shown in FIG. 16;
• wherein the antibody specifically binds to osteoprotegerin ligand (OPGL).

An isolated human antibody comprising:

• a. human heavy chain framework regions, a human heavy chain CDR1 region, a human heavy chain CDR2 region, and a human heavy chain CDR3 region, wherein the human heavy chain CDR3 region is the heavy chain CDR3 region of 2E11 or 18B2, as shown in FIG. 15;
• and
• b. human light chain framework regions, a human light chain CDR1 region, a human light chain CDR2 region, and a human light chain CDR3 region, wherein the human light chain CDR3 region is the light chain CDR3 region of 2E11 or 18B2 as shown in FIG. 16;
• wherein the antibody specifically binds to osteoprotegerin ligand (OPGL).