Anti-GDF15 antibodies
Monoclonal antibodies that bind and inhibit the activity of human GDF15 are disclosed. The antibodies can be used to treat body weight loss, including cachexia, associated with the over-expression of human GDF15.
1. An isolated antibody that binds human GDF15 comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region selected from the group consisting of:
(a) (i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:234 (Hu01G06 IGHV1-69 F1), a CDR H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:238 and SEQ ID NO:241 (Hu01G06 IGHV1-69 F1), and a CDR H3 comprising the amino acid sequence of SEQ ID NO:15 (Hu01G06 IGHV1-69 F1), wherein the CDR sequences are interposed between framework sequences having at least 95% identity to the framework sequences of SEQ ID NO:250 (Hu01G06 IGHV1-69 F1); and
(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO:21 (Hu01G06 IGKV1-39 F1), a CDR L2 comprising the amino acid sequence of SEQ ID NO:26 (Hu01G06 IGKV1-39 F1), and a CDR L3 comprising the amino acid sequence of SEQ ID NO:32, wherein the CDR sequences are interposed between framework sequences having at least 95% identity to the framework sequences of SEQ ID NO:92 (Hu01G06 IGKV1-39 F1); and
(b) (i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:38 (Hu01G06 IGHV1-18 F2), a CDR H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:237 and SEQ ID NO:241 (Hu01G06 IGHV1-18 F2), and a CDR H3 comprising the amino acid sequence of SEQ ID NO:15 (Hu01G06 IGHV1-18 F2), wherein the CDR sequences are interposed between framework sequences having at least 95% identity to the framework sequences of SEQ ID NO:248 (Hu01G06 IGHV1-18 F2); and
(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO:21 (Hu01G06 IGKV1-39 F2), a CDR L2 comprising the amino acid sequence of SEQ ID NO:26 (Hu01G06 IGKV1-39 F2), and a CDR L3 comprising the amino acid sequence of SEQ ID NO:244 (Hu01G06 IGKV1-39 F2) wherein the CDR sequences are interposed between framework sequences having at least 95% identity to the framework sequences of SEQ ID NO:254 (Hu01G06 IGKV1-39 F2).
2. The antibody of claim 1 , wherein the antibody comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region selected from the group consisting of:
(a) (i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:234 (Hu01G06 IGHV1-69 F1), a CDR H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:238 and SEQ ID NO:241 (Hu01G06 IGHV1-69 F1), and a CDR H3 comprising the amino acid sequence of SEQ ID NO:15 (Hu01G06 IGHV1-69 F1), wherein the CDR sequences are interposed between framework sequences having at least 98% identity to the framework sequences of SEQ ID NO:250 (Hu01G06 IGHV1-69 F1); and
(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO:21 (Hu01G06 IGKV1-39 F1), a CDR L2 comprising the amino acid sequence of SEQ ID NO:26 (Hu01G06 IGKV1-39 F1), and a CDR L3 comprising the amino acid sequence of SEQ ID NO:32, wherein the CDR sequences are interposed between framework sequences having at least 98% identity to the framework sequences of SEQ ID NO:92 (Hu01G06 IGKV1-39 F1); and
(b) (i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:38 (Hu01G06 IGHV1-18 F2), a CDR H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:237 and SEQ ID NO:241 (Hu01G06 IGHV1-18 F2), and a CDR H3 comprising the amino acid sequence of SEQ ID NO:15 (Hu01G06 IGHV1-18 F2), wherein the CDR sequences are interposed between framework sequences having at least 98% identity to the framework sequences of SEQ ID NO:248 (Hu01G06 IGHV1-18 F2); and
(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO:21 (Hu01G06 IGKV1-39 F2), a CDR L2 comprising the amino acid sequence of SEQ ID NO:26 (Hu01G06 IGKV1-39 F2), and a CDR L3 comprising the amino acid sequence of SEQ ID NO:244 (Hu01G06 IGKV1-39 F2) wherein the CDR sequences are interposed between framework sequences having at least 98% identity to the framework sequences of SEQ ID NO:254 (Hu01G06 IGKV1-39 F2).
3. The antibody of claim 1 , wherein the antibody comprises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region selected from the group consisting of:
(a) (i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:234 (Hu01G06 IGHV1-69 F1), a CDR H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:238 and SEQ ID NO:241 (Hu01G06 IGHV1-69 F1), and a CDR H3 comprising the amino acid sequence of SEQ ID NO:15 (Hu01G06 IGHV1-69 F1), wherein the CDR sequences are interposed between framework sequences having at least 99% identity to the framework sequences of SEQ ID NO:250 (Hu01G06 IGHV1-69 F1); and
(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO:21 (Hu01G06 IGKV1-39 F1), a CDR L2 comprising the amino acid sequence of SEQ ID NO:26 (Hu01G06 IGKV1-39 F1), and a CDR L3 comprising the amino acid sequence of SEQ ID NO:32, wherein the CDR sequences are interposed between framework sequences having at least 99% identity to the framework sequences of SEQ ID NO:92 (Hu01G06 IGKV1-39 F1); and
(b) (i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:38 (Hu01G06 IGHV1-18 F2), a CDR H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:237 and SEQ ID NO:241 (Hu01G06 IGHV1-18 F2), and a CDR H3 comprising the amino acid sequence of SEQ ID NO:15 (Hu01G06 IGHV1-18 F2), wherein the CDR sequences are interposed between framework sequences having at least 99% identity to the framework sequences of SEQ ID NO:248 (Hu01G06 IGHV1-18 F2); and
(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO:21 (Hu01G06 IGKV1-39 F2), a CDR L2 comprising the amino acid sequence of SEQ ID NO:26 (Hu01G06 IGKV1-39 F2), and a CDR L3 comprising the amino acid sequence of SEQ ID NO:244 (Hu01G06 IGKV1-39 F2) wherein the CDR sequences are interposed between framework sequences having at least 99% identity to the framework sequences of SEQ ID NO:254 (Hu01G06 IGKV1-39 F2).
4. The antibody of claim 1 , wherein the antibody has a K D of 300 pM or lower, as measured by surface plasmon resonance or bio-layer interferometry.
5. The antibody of claim 1 , wherein the antibody has a K D of 150 pM or lower, as measured by surface plasmon resonance or bio-layer interferometry.
6. The antibody of claim 1 , wherein the antibody has a K D of 100 pM or lower, as measured by surface plasmon resonance or bio-layer interferometry.
7. An isolated nucleic acid comprising a nucleotide sequence encoding an immunoglobulin heavy chain variable region or immunoglobulin light chain variable region of claim 1 .
8. An expression vector comprising the nucleic acid of claim 7 .
9. A host cell comprising the expression vector of claim 8 .