BOVINE FUSION ANTIBODIES

• US 20140227267A1
• Filed: 01/10/2014
• Published: 08/14/2014
• Est. Priority Date: 01/11/2013
• Status: Active Grant

• Current Assignee: The Scripps Research Institute
• Original Assignee: The California Institute For Biomedical Research
• Inventors: Schultz, Peter G., WANG, Feng, ZHANG, Yong
• Granted Patent: US 9,644,021 B2
• Time in Patent Office: Days
• US Class Current: 424/134.1
• CPC Class Codes: C07K 14/575 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695
• CPC Class Codes: C07K 14/5759 Products of obesity genes, e.g. leptin, obese (OB), tub, fat
• CPC Class Codes: C07K 14/605 Glucagons
• CPC Class Codes: C07K 14/61 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: C07K 14/635 Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
• CPC Class Codes: C07K 14/64 Relaxins
• CPC Class Codes: C07K 14/811 Serine protease (E.C. 3.4.21) inhibitors
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/2869 against hormone receptors for antibodies against neuromediator receptors C07K16/286
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2318/10 Immunoglobulin or domain(s) thereof as scaffolds for inserted non-Ig peptide sequences, e.g. for vaccination purposes
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68

Abstract

Disclosed herein are immunoglobulin constructs comprising at least one immunoglobulin domain or fragment thereof; and a therapeutic polypeptide or derivative or variant thereof attached to or inserted into said immunoglobulin domain. Also provided are immunoglobulin constructs comprising a mammalian immunoglobulin heavy chain comprising at least a portion of a knob domain in the complementarity-determining region 3 (CDR3H) or fragment thereof; and a therapeutic polypeptide attached to or inserted into said knob domain of the CDR3H. Also provided are immunoglobulin constructs comprising a mammalian immunoglobulin heavy chain comprising at least a portion of a stalk domain in the complementarity-determining region 3 (CDR3H) or fragment thereof; and a therapeutic polypeptide attached to or inserted into said stalk domain of the CDR3H. Also described herein are methods and compositions comprising the immunoglobulin constructs described herein for treatment and prevention of a disease or condition in a subject.

Claims

1-132. -132. (canceled)

133. An antibody fusion comprising:

(a) a first antibody sequence, wherein at least a portion of the first antibody sequence is derived from an antibody comprising an ultralong complementarity determining region 3 (CDR3); and

(b) a non-antibody sequence, wherein the non-antibody sequence is derived from a polypeptide selected from a group consisting of Mamba1, oxyntomodulin, 550 peptide, Amgen 1, and parathyroid hormone.

134. The antibody fusion of claim 133, wherein the antibody comprising the ultralong CDR3 is a bovine antibody.

135. The antibody fusion of claim 134, wherein the bovine antibody is BLV1H12, BLV5B8, BLVCV1, BLV5D3, BLV8C11, BF1H1, or F18.

136. The antibody fusion of claim 133, wherein the first antibody sequence is derived from a heavy chain of the antibody comprising the ultralong CDR3.

137. The antibody fusion of claim 133, wherein the antibody comprising the ultralong CDR3 comprises an amino acid sequence that is at least 50% homologous to SEQ ID NO:

9 or is encoded by a nucleotide sequence that is at least 50% homologous to SEQ ID NO;

2.

138. The antibody fusion of claim 133, wherein the non-antibody sequence replaces at least a portion of the ultralong CDR3.

139. The antibody fusion of claim 133, wherein the non-antibody sequence is inserted into the first antibody sequence.

140. The antibody fusion of claim 133, wherein the antibody fusion comprises an amino acid sequence that is at least 50% homologous to SEQ ID NOs:

10-14 or is encoded by a nucleotide sequence that is at least 50% homologous to SEQ ID NOs;

3-7.

141. The antibody fusion of claim 133, further comprising a second antibody sequence.

142. The antibody fusion of claim 141, wherein the second antibody sequence comprises an amino acid sequence that is at least 50% homologous to SEQ ID NO:

8 or is encoded by a nucleotide sequence that is at least 50% homologous to SEQ ID NO;

1.

143. The antibody fusion of claim 133, further comprising a first linker sequence.

144. The antibody fusion of claim 143, further comprising a second linker sequence.

145. The antibody fusion of claim 144, wherein the first linker sequence attaches the non-antibody sequence to the first antibody sequence, the second linker sequence attaches the non-antibody sequence to the first antibody sequence, or both the first and second linker sequences attach the non-antibody sequence to the first antibody sequence.

146. The antibody fusion of claim 144, wherein the first linker sequence comprises a sequence selected from SEQ ID NOs:

15-17, 103, and 129, the second linker sequence comprises a sequence selected from SEQ ID NOs;

15-17, 103, and 129, or both the first and second linker sequences each independently comprise a sequence selected from SEQ ID NOs;

15-17, 103, and 129.

147. The antibody fusion of claim 133, further comprising one or more proteolytic cleavage sites.

148. The antibody fusion of claim 147, wherein the one or more proteolytic cleavage sites comprises SEQ ID NO:

104.

152. A method of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject the antibody fusion of claim 133.

153. The method of claim 152, wherein the disease or condition is selected from a group comprising autoimmune disease, heteroimmune disease or condition, inflammatory disease, pathogenic infection, thromboembolic disorder, respiratory disease or condition, metabolic disease, central nervous system (CNS) disorder, bone disease, cancer, blood disorder, obesity, diabetes, osteoporosis, anemia, or pain.

154. The method of claim 152, wherein the disease or condition would benefit from modulation of an ion channel.

155. The method of claim 154, wherein the ion channel is selected from the group comprising Kv1.3 ion channel, Nav1.7 ion channel and acid sensing ion channel (ASIC).

156. The method of claim 152, wherein the disease or condition would benefit from the modulation of a receptor.

157. The method of claim 156, wherein the receptor is selected from the group comprising GLP1R, GCGR and parathyroid hormone receptor.

149. A vector comprising a polynucleotide comprising a sequence that is at least 50% homologous to SEQ ID NOs:

3-7 or a sequence that encodes for an amino acid that is at least 50% homologous to SEQ ID NOs;

10-14.

150. A host cell comprising a polynucleotide comprising a sequence that is at least 50% homologous to SEQ ID NOs:

3-7 or expressing an amino acid that is at least 50% homologous to SEQ ID NOs;

10-14.

151. A method of producing an antibody fusion, the method comprising culturing the host cell of claim 150 under conditions wherein the host cell expresses the polynucleotide comprising the sequence that is at least 50% homologous to SEQ ID NOs:

3-7 or the host cell produces the amino acid that is at least 50% homologous to SEQ ID NOs;

10-14.