Immunological Reagents

• US 20170166642A1
• Filed: 09/22/2016
• Published: 06/15/2017
• Est. Priority Date: 08/05/2014
• Status: Active Grant

• Current Assignee: MabQuest S.A.
• Original Assignee: MabQuest S.A.
• Inventors: Pantaleo, Giuseppe, Fenwick, Craig
• Granted Patent: US 9,982,052 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: C07K 16/1063 env, e.g. gp41, gp110/120, gp160, V3, PND, CD4 binding site
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 multispecific
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/74 Inducing cell proliferation
• CPC Class Codes: C07K 2317/75 Agonist effect on antigen
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere

Abstract

This disclosure relates to binding agents with specificity for programmed cell death 1 (PD-1) and to methods for using the same to treat, prevent and/or ameliorate an infectious disease (e.g., human immunodeficiency virus (HIV)), cancer and/or autoimmunity. In addition, this disclosure identifies a novel binding patch (“P2”) on PD-1 that is linked with a previously unidentified functional activity of PD-1 that is distinct from the interaction site involved with either the PD-L1 or PD-L2 ligands. Furthermore, we demonstrate that antibodies that interact with this region of PD-1 are able to act as antagonists of PD-1 and that this antagonism is further enhanced with the addition of antibodies that act through the blockade of the PD-1/PD-L1/L2 interaction.

Claims

1-148. -148. (canceled)

149. A binding agent that binds programmed cell death 1 (PD1) comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOS. 1-138 and/or shown in Tables 1A and/or 1B.

150. The binding agent of claim 149 that is an isolated monoclonal antibody.

151. The binding agent of claim 149 comprising at least one heavy chain CDR1 amino acid sequence selected from the group consisting of SEQ ID NOS. 1-23;

and/or at least one light chain CDR1 amino acid sequence selected from the group consisting of SEQ ID NOS. 70-92.

152. The binding agent of claim 149 comprising at least one heavy chain CDR2 amino acid sequence selected from the group consisting of SEQ ID NOS. 24-46;

and/or at least one light chain CDR2 amino acid sequence selected from the group consisting of SEQ ID NOS. 93-115.

153. The binding agent of claim 149 comprising at least one heavy chain CDR3 amino acid sequence selected from the group consisting of SEQ ID NOS. 47-69;

and/or at least one light chain CDR3 amino acid sequence selected from the group consisting of SEQ ID NOS. 116-138.

154. The binding agent of claim 149 comprising the amino acid sequences selected from the group consisting of:

155. The binding agent of claim 154 comprising a combination of amino acid sequences, the combination being selected from the group consisting of:

SEQ ID NOS. 1, 24, 47, 70, 93, and 116;

SEQ ID NOS. 2, 25, 48, 71, 94, and 117;

SEQ ID NOS. 3, 26, 49, 72, 95, and 118;

SEQ ID NOS. 4, 27, 50, 73, 96, and 119;

SEQ ID NOS. 5, 28, 51, 74, 97, and 120;

SEQ ID NOS. 6, 29, 52, 75, 98, and 121;

SEQ ID NOS. 7, 30, 53, 76, 99, and 122;

SEQ ID NOS. 8, 31, 54, 77, 100, and 123;

SEQ ID NOS. 9, 32, 55, 78, 101, and 124;

SEQ ID NOS. 10, 33, 56, 79, 102, and 125;

SEQ ID NOS. 11, 34, 57, 80, 103, and 126;

SEQ ID NOS. 12, 35, 58, 81, 104, and 127;

SEQ ID NOS. 13, 36, 59, 82, 105, and 128;

SEQ ID NOS. 14, 37, 60, 83, 106, and 129;

SEQ ID NOS. 15, 38, 61, 84, 107, and 130;

SEQ ID NOS. 16, 39, 62, 85, 108, and 131;

SEQ ID NOS. 17, 40, 63, 86, 109, and 132;

SEQ ID NOS. 18, 41, 64, 87, 110, and 133;

SEQ ID NOS. 19, 42, 65, 88, 111, and 134;

SEQ ID NOS. 20, 43, 66, 89, 112, and 135;

SEQ ID NOS. 21, 44, 67, 90, 113, and 136;

SEQ ID NOS. 22, 45, 68, 91, 114, and 137; and

,

SEQ ID NOS. 23, 46, 69, 92, 115, and 138.

156. An isolated polynucleotide encoding a binding agent of claim 149, or an expression vector or host cell comprising the same.

157. A composition comprising at least one binding agent of claim 149 and a pharmaceutically acceptable carrier.

158. A method for treating, preventing and/or ameliorating an infectious disease, cancer and/or autoimmunity in a mammal comprising administering to the mammal at least one effective dose of a pharmaceutical composition comprising a binding agent of claim 149.

163. The binding agent of claim 149 comprising a combination of amino acid sequences selected from the group consisting of SEQ ID NOS. 17, 40, 63, 86, 109, and 132 (135C12);

SEQ ID NOS. 2, 25, 48, 71, 94, and 117 (139D6);

SEQ ID NOS. 19, 42, 65, 88, 111, and 134 (136B4); and

, SEQ ID NOS. 3, 26, 49, 72, 95, and 118 (135D1).

164. A method for treating, preventing and/or ameliorating an infectious disease, cancer and/or autoimmunity in a mammal comprising administering to the mammal at least one effective dose of a pharmaceutical composition comprising a binding agent of claim 149.

159. A binding agent that binds programmed cell death 1 (PD-1), the binding agent comprising one or more amino acid sequences selected from the group consisting of:

160. The binding agent of claim 159 comprising SEQ ID NOS. 170 and 178;

SEQ ID NOS. 171 and 179;

SEQ ID NOS. 172 and 180;

SEQ ID NOS. 173 and 181;

SEQ ID NOS. 174 and 182;

SEQ ID NOS. 175 and 183;

SEQ ID NOS. 176 and 184;

SEQ ID NOS. 186 and 195;

SEQ ID NOS. 187 and 196;

SEQ ID NOS. 188 and 197;

SEQ ID NOS. 189 and 198;

SEQ ID NOS. 190 and 199;

SEQ ID NOS. 191 and 200;

SEQ ID NOS. 192 and 201;

SEQ ID NOS. 193 and 202.

161. A binding agent of claim 160 that exhibits approximately the binding affinities (ka (M⁻

1/s<sup>−

1</sup>), kd (s<sup>−

1</sup>), and KD (M)) for human and monkey PD-1 as any of humanized antibody A35796 (comprising SEQ ID NOS. 170 and

     178), humanized antibody A35793 (comprising SEQ ID NOS. 171 and

     179), humanized antibody A35818 (comprising SEQ ID NOS. 172 and

     180), humanized antibody A35795 (comprising SEQ ID NOS. 173 and

     181), humanized antibody A35797 (comprising SEQ ID NOS. 174 and

     182), humanized antibody A35799 (comprising SEQ ID NOS. 175 and

     183), or humanized antibody A35805 (comprising SEQ ID NOS. 176 and

     184), as shown below;

162. A binding agent of claim 161 that exhibits approximately the binding affinities (ka (M⁻

1/s<sup>−

1</sup>), kd (s<sup>−

1</sup>), and KD (M)) for human and monkey PD-1 as any of humanized antibodies A35775 comprising SEQ ID NOS. 186 and 195;

A35783 comprising SEQ ID NOS. 187 and 196;

A35774 comprising SEQ ID NOS. 188 and 197;

A36443 comprising SEQ ID NOS. 189 and 198;

A35777 comprising SEQ ID NOS. 190 and 199;

A35789 comprising SEQ ID NOS. 191 and 200;

A36448 comprising SEQ ID NOS. 192 and 201;

or A36437 comprising SEQ ID NOS. 193 and 202;

as shown below;

165. A method for treating, preventing and/or ameliorating an infectious disease, cancer and/or autoimmunity in a mammal comprising administering to the mammal at least one effective dose of a pharmaceutical composition comprising a binding agent of claim 159.