Anti-PACAP antibodies and uses thereof

Patent metadata

Field	Value
Publication number	US-11352409-B2
Application number	US-201916272406-A
Country	US
Kind code	B2
Filing date	Feb 11, 2019
Priority date	Apr 15, 2016
Publication date	Jun 7, 2022
Grant date	Jun 7, 2022

Abstract

The present invention is directed to antibodies and antigen binding fragments thereof having binding specificity for PACAP. The antibodies and antigen binding fragments thereof comprise the sequences of the VH, VL, and CDR polypeptides described herein, and the polynucleotides encoding them. Antibodies and antigen binding fragments described herein bind to and/or compete for binding to the same linear or conformational epitope(s) on human PACAP as an anti-PACAP antibody. The invention contemplates conjugates of anti-PACAP antibodies and binding fragments thereof conjugated to one or more functional or detectable moieties. Methods of making said anti-PACAP antibodies and antigen binding fragments thereof are also contemplated. Other embodiments of the invention contemplate using anti-PACAP antibodies, and binding fragments thereof, for the diagnosis, assessment, and treatment of diseases and disorders associated with PACAP and conditions where antagonism of PACAP-related activities, such as vasodilation, photophobia, mast cell degranulation, and/or neuronal activation, would be therapeutically beneficial.

First claim

What is claimed is:

1. A humanized anti-pituitary adenylate cyclase-activating peptide (anti-PACAP) antibody or antigen-binding antibody fragment thereof, comprising: (i) a heavy chain variable region (V H ) comprising a complementarity-determining region 1 (CDR1) sequence consisting of the amino acid sequence of SEQ ID NO: 1164, a complementarity-determining region 2 (CDR2) sequence consisting of the amino acid sequence of SEQ ID NO: 1166, and a complementarity-determining region 3 (CDR3) sequence consisting of the amino acid sequence of SEQ ID NO: 1168; and (ii) a light chain variable region (VL) comprising a CDR1 sequence consisting of the amino acid sequence of SEQ ID NO: 1184, a CDR2 sequence consisting of the amino acid sequence of SEQ ID NO: 1186, and a CDR3 sequence consisting of the amino acid sequence of SEQ ID NO: 1188, wherein: (i) the V H comprises an amino acid sequence with at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 1162, and (ii) the VL comprises an amino acid sequence with at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 1182, wherein said antibody or antigen-binding antibody fragment thereof binds to an epitope which comprises residues 7, 10, 12, 13, 14 and 17 of human PACAP38 comprising the amino acid sequence of SEQ ID NO: 1241 or of human PACAP27 comprising the amino acid sequence of SEQ ID NO: 1242, and optionally wherein said epitope is identified by alanine scanning.

2. The humanized anti-PACAP antibody or antigen-binding antibody fragment thereof according to claim 1 , wherein:
(i) the V H comprises an amino acid sequence with at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1162 and comprises a CDR1 sequence consisting of the amino acid sequence of SEQ ID NO: 1164, a CDR2 sequence consisting of SEQ ID NO: 1166, and a CDR3 sequence consisting of the amino acid sequence of SEQ ID NO: 1168; and
(ii) the VL comprises an amino acid sequence with at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1182 and comprises a CDR1 sequence consisting of the amino acid sequence of SEQ ID NO: 1184, a CDR2 sequence consisting of the amino acid sequence of SEQ ID NO: 1186, and a CDR3 sequence consisting of the amino acid sequence of SEQ ID NO: 1188.

3. The humanized anti-PACAP antibody or antigen-binding antibody fragment thereof according to claim 1 , wherein:
(i) the V H comprises an amino acid sequence with at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1162 and comprises a CDR1 sequence consisting of the amino acid sequence of SEQ ID NO: 1164, a CDR2 sequence consisting of SEQ ID NO: 1166, and a CDR3 sequence consisting of the amino acid sequence of SEQ ID NO: 1168; and
(ii) the VL comprises an amino acid sequence with at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1182 and comprises a CDR1 sequence consisting of the amino acid sequence of SEQ ID NO: 1184, a CDR2 sequence consisting of the amino acid sequence of SEQ ID NO: 1186, and a CDR3 sequence consisting of the amino acid sequence of SEQ ID NO: 1188.

4. The humanized anti-PACAP antibody or antigen-binding antibody fragment thereof according to claim 1 , wherein:
(i) the V H comprises an amino acid sequence with at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 1162 and comprises a CDR1 sequence consisting of the amino acid sequence of SEQ ID NO: 1164, a CDR2 sequence consisting of SEQ ID NO: 1166, and a CDR3 sequence consisting of the amino acid sequence of SEQ ID NO: 1168; and
(ii) the VL comprises an amino acid sequence with at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 1182 and comprises a CDR1 sequence consisting of the amino acid sequence of SEQ ID NO: 1184, a CDR2 sequence consisting of the amino acid sequence of SEQ ID NO: 1186, and a CDR3 sequence consisting of the amino acid sequence of SEQ ID NO: 1188.

5. The humanized anti-PACAP antibody or antigen-binding antibody fragment thereof according to claim 1 , wherein:
(i) the V H comprises the amino acid sequence of SEQ ID NO: 1162; and
(ii) the VL comprises the amino acid sequence of SEQ ID NO: 1182.

6. The humanized anti-PACAP antibody according to claim 1 , comprising:
(i) a heavy chain comprising an amino acid sequence with at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1161; and
(ii) a light chain comprising an amino acid sequence with at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1181,

wherein:
(i) the heavy chain comprises said V H , and said V H comprises a CDR1 sequence consisting of the amino acid sequence of SEQ ID NO: 1164, a CDR2 sequence consisting of SEQ ID NO: 1166, and a CDR3 sequence consisting of the amino acid sequence of SEQ ID NO: 1168; and
(ii) the light chain comprises said VL, and said VL comprises a CDR1 sequence consisting of the amino acid sequence of SEQ ID NO: 1184, a CDR2 sequence consisting of the amino acid sequence of SEQ ID NO: 1186, and a CDR3 sequence consisting of the amino acid sequence of SEQ ID NO: 1188.

7. The humanized anti-PACAP antibody according to claim 6 , wherein:
(i) the heavy chain comprises the amino acid sequence of SEQ ID NO: 1161; and
(ii) the light chain comprises the amino acid sequence of SEQ ID NO: 1181.

8. The humanized anti-PACAP antibody according to claim 1 , comprising a human IgG constant domain, optionally wherein the human IgG is IgG1, IgG2, IgG3, or IgG4.

9. The humanized anti-PACAP antibody according to claim 1 , wherein the antibody comprises a Fc region comprising the amino acid sequence of SEQ ID NO: 1244, 1245, or 1246.

10. The humanized anti-PACAP antibody according to claim 1 , wherein the antibody comprises an Fc region which
(i) lacks N-glycosylation;
(ii) lacks O-glycosylation; or
(iii) lacks N-glycosylation and O-glycosylation.

11. The humanized anti-PACAP antigen-binding antibody fragment thereof according to claim 1 , wherein the antigen-binding antibody fragment is selected from the group consisting of scFvs, fragment antigen-binding (Fab) fragments, Fab′ fragments, monovalent antigen-binding antibody fragments, and F(ab′) 2 fragments, wherein said antigen-binding antibody fragments comprise a heavy chain variable region (V H ) and a light chain variable region (VL) comprising complementarity-determining regions according to claim 1 .

12. The humanized anti-PACAP antibody or antigen-binding antibody fragment thereof according to claim 1 , which binds to adenylate cyclase-activating peptide (PACAP) with:
(i) a dissociation constant (K D ) of less than or equal to 5×10 −10 M, optionally wherein the KD is determined by ELISA, bio-layer interferometry, kinetic exclusion assay, or surface plasmon resonance at 25° or 37° C.; or
(ii) an off-rate (kd) of less than or equal to 5×10 −4 s −1 .

13. The humanized anti-PACAP antibody or antigen-binding antibody fragment thereof according to claim 1 , wherein the K D of said antibody or antigen-binding antibody fragment thereof for PACAP is at least 10-fold lower than the K D of said antibody or antigen-binding antibody fragment thereof for Vasoactive Intestinal Peptide (VIP).

14. The humanized anti-PACAP antibody or antigen-binding antibody fragment thereof according to claim 1 , which inhibits at least one biological effect elicited by PACAP, wherein said at least one biological effect is:
(i) PACAP-induced cAMP production;
(ii) PACAP-induced vasodilation in a subject administered with said antibody or antigen-binding antibody fragment; or
(iii) PACAP-induced photophobia in a subject administered with said antibody o

Assignees

• H Lundbeck As

Inventors

• Loomis Maria-Cristina
• Garcia-Martinez Leon
• Dutzar Benjamin H
• Allison Daniel S
• Hendrix Katherine Lee
• Ojala Ethan W
• Fan Pei
• Smith Jeffrey T L
• Latham John A
• Karasek Charlie
• Mulligan Jenny
• Scalley-Kim Michelle
• Stewart Erica
• Rubin Vanessa Lisbeth
• Billgren Jens J

Classifications

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• G01N2333/575

  Hormones · CPC title

• G01N33/6854

  Immunoglobulins · CPC title

• C12N15/63

  Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression · CPC title

• C12N15/09

  Recombinant DNA-technology · CPC title