Antibodies to IL-15

• US 10,301,384 B2
• Filed: 07/01/2015
• Issued: 05/28/2019
• Est. Priority Date: 07/02/2014
• Status: Active Grant

• Current Assignee: Calypso Biotech SA (Calypso Biotech BV)
• Original Assignee: Calypso Biotech SA (Calypso Biotech BV)
• Inventors: Vicari, Alain, Leger, Olivier
• Primary Examiner(s): Mertz, Prema M
• Application Number:
  US15/320,763
• Publication Number:
  US 20170137511A1
• Time in Patent Office: 1,427 Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07K 16/244 Interleukins [IL]
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/33 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 2317/56 : variable (Fv) region, i.e. VH and/or VL
• 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 2333/5443 : IL-15
• CPC Class Codes: G01N 2333/7155 : for interleukins [IL]
• CPC Class Codes: G01N 33/6869 : Interleukin
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention relates to antibodies binding IL-15, in particular humanized antibodies. In particular, the anti-IL-15 antibodies according to the invention are able to neutralize IL-15 activity and are useful in the prevention and/or treatment of an autoimmune disease and/or inflammatory disorder, a malignancy, transplant rejection, metabolic condition and/or an infectious disease caused by parasitic, viral or bacterial pathogens.

Claims

1. An isolated antibody binding IL-15 comprising:

a) a heavy chain variable region comprising SEQ ID NO;

5 or any variant thereof wherein 1, 2, 3, 4, 5 or 6 amino acids selected from arginine (R) at position H3 (VH RH3), methionine (M) at position H5 (VH MH5), alanine (A) at position H6 (VH AH6), alanine (A) at position H49 (VH AH49), aspartic acid (D) at position H61 (VH DH61), serine (S) at position H62 (VH SH62), methionine (M) at position H98 (VH MH98), tryptophan (W) at position H100C (VH WH100C), and methionine (M) at position H100E (VH MH100E) are substituted by a different amino acid, and

b) a light chain variable region comprising SEQ ID NO;

24 or any variant thereof wherein 1, 2, 3, or 4 amino acids selected from tyrosine (Y) at position L36 (VL YL36), leucine (L) at position L46 (VL LL46), aspartic acid (D) at position L91 (VL DL91) and serine (S) at position L92 (VL SL92) are substituted by a different amino acid,

or an antigen-binding fragment thereof.

2. The isolated antibody or antigen-binding fragment thereof according to claim 1, comprising:

(1) a heavy chain variable region comprising SEQ ID NO;

5 or any variant thereof having at least 95% identity with SEQ ID NO;

5, and

(2) a light chain variable region comprising SEQ ID NO;

24 or any variant thereof having at least 95% identity with SEQ ID NO;

24,

or an antigen-binding fragment thereof.

3. The isolated antibody according to claim 1, which is a humanized antibody.

4. The isolated antibody or antigen-binding fragment thereof according to claim 1, wherein:

(1) said variant of SEQ ID NO;

5 has-comprising the amino acid sequence of SEQ ID NO;

5 except that;

(i) VH RH3 is substituted by glutamine (Q), and/or VH MH5 is substituted by valine (V), and/or VH AH6 is substituted by glutamic acid (E), and/or VH AH49 is substituted by serine (S), and/or

(ii) VH DH61 is substituted by glutamic acid (E), and/or VH SH62 is substituted by threonine (T), and/or

(iii) VH MH98 is substituted by leucine (L), phenylalanine (F), isoleucine (1), or alanine (A), and/or VH WH100C is substituted by tyrosine (Y), phenylalanine (F), or alanine (A), and/or VH MH100E is substituted by leucine (L), phenylalanine (F), or isoleucine (I), and/or

(2) said variant of SEQ ID NO;

24 comprising the amino acid sequence of SEQ ID NO;

24 except that;

(i) VL YL36 is substituted by phenylalanine (F), and/or VL LL46 is substituted by arginine (R), and/or

(ii) VL DL91 is substituted by glutamic acid (E), and/or VL SL92 is substituted by threonine (T).

5. The isolated antibody or antigen-binding fragment thereof according to claim 1, comprising:

(1) a heavy chain variable region comprising SEQ ID NO;

5 except that;

(i) VH RH3 is substituted by glutamine (Q), and/or VH MH5 is substituted by valine (V), and/or VH AH6 is substituted by glutamic acid (E), and/or

(ii) VH SH62 is substituted by threonine (T), and/or

(iii) VH WH100C is substituted by tyrosine (Y), and

(2) a light chain variable region comprising SEQ ID NO;

1.

6. The isolated antibody or antigen-binding fragment thereof according to claim 1, comprising:

(1) a heavy chain variable region selected from;

SEQ ID NO;

6, SEQ ID NO;

12, SEQ ID NO;

21, and SEQ ID NO;

5, and

(2) a light chain variable region comprising SEQ ID NO;

24.

7. The isolated antibody or antigen-binding fragment thereof according to claim 1, comprising a heavy chain variable region of SEQ ID NO:

6 and a light chain variable region comprising SEQ ID NO;

24.

8. The isolated antibody or antigen-binding fragment thereof according to claim 1, which inhibits IL-15 activity.

9. A pharmaceutical composition comprising one or more of:

(i) an antibody binding to IL-15 or antigen-binding fragment thereof according to claim 1 and at least one pharmaceutically acceptable carrier.

10. An ex vivo method for detecting the presence and/or concentration of IL-15 protein in a biological sample, comprising the steps of:

(i) Providing a biological sample from a subject,

(ii) Reacting said biological sample with at least one antibody or antigen-binding fragment thereof according to claim 1, under conditions sufficient for binding IL-15 protein present in said biological sample to said at least one antibody or fragment thereof through antigen-antibody interactions; and

(iii) Detecting a signal proportional to the level of antigen-antibody complex formed in step (ii),

wherein the intensity of the signal correlates with the concentration of IL-15 protein in the biological sample.

11. The isolated antibody according to claim 1, comprising:

(1) a heavy chain variable region comprising a variant of SEQ ID NO;

5 wherein;

(i) arginine (R) at position H3 (VH RH3), methionine (M) at position H5 (VH MH5), alanine (A) at position H6 (VH AH6) within the heavy chain variable framework region, or

(ii) arginine (R) at position H3 (VH RH3), methionine (M) at position H5 (VH MH5), alanine (A) at position H6 (VH AH6), within the heavy chain variable framework region, and tryptophan (W) at position H100C (VH WH100C) within the heavy chain CDR3, or

(iii) serine (S) at position H62 (VH SH62), within the heavy chain CDR2, and tryptophan (W) at position H100C (VH WH100C) within the heavy chain CDR3,

are substituted by a different amino acid, and

(2) a light chain variable region comprising SEQ ID NO;

24.