AGONISTIC ANTIBODIES THAT BIND HUMAN CD40 AND USES THEREOF

• US 20190322743A1
• Filed: 04/05/2019
• Published: 10/24/2019
• Est. Priority Date: 04/18/2016
• Status: Active Grant

• Current Assignee: Celldex Therapeutics Incorporated
• Original Assignee: Celldex Therapeutics Incorporated
• Inventors: KELER, Tibor, GOLDSTEIN, Joel, VITALE, Laura A., HE, Lizhen, O'NEILL, Tom, CROCKER, Andrea, SUNDARAPANDIYAN, Karuna, THOMAS, Lawrence J., WIDGER, Jenifer
• Granted Patent: US 10,633,444 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 39/385 Haptens or antigens, bound to carriers
• CPC Class Codes: A61K 39/39541 against normal tissues, cells
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: C07K 14/54 Interleukins [IL]
• CPC Class Codes: C07K 14/70575 NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154 NGF C07K14/48, TNF C07K14/525
• CPC Class Codes: C07K 14/715 for cytokines; for lymphokines; for interferons
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2878 against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• 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 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/74 Inducing cell proliferation
• CPC Class Codes: C07K 2317/75 Agonist effect on antigen
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

Isolated monoclonal agonistic antibodies which bind to human CD40 and related antibody-based compositions and molecules are disclosed. Also disclosed are therapeutic and diagnostic methods for using the antibodies.

Claims

1. An agonistic isolated monoclonal antibody that binds to human CD40, wherein the antibody directly activates antigen presenting cells (APCs) and/or increases an immune response to an antigen either:

(a) independent of Fc receptor binding;

(b) without inducing antibody-dependent cellular cytotoxicity (ADCC) of CD40 expressing cells;

(c) without inducing complement dependent cellular cytotoxicity (CDC) of CD40 expressing cells; and

/or

(d) independent of Fc receptor binding and is capable of synergizing with CD40L.

10. The antibody of claim 1, wherein the antibody binds to one or more residues within amino acid residues 1-5 and 33-36 of the extracellular domain (ECD) of human CD40 (SEQ ID NO:

133).

11. The antibody of claim 10, which further binds to one or more amino acids selected from the group consisting of amino acids 25, 26, 28 and 30 of the ECD of human CD40 (SEQ ID NO:

133).

12. The antibody of claim 10, which binds to one or more amino acids selected from the group consisting of amino acids 5, 33, 34 and 36 of the ECD of human CD40 (SEQ ID NO:

133).

13. The antibody of claim 12, which binds to amino acids 5, 33 and 36 of the ECD of human CD40 (SEQ ID NO:

133).

14. The antibody of claim 13, which binds to amino acids 5, 33, 34 and 36 of the ECD of human CD40 (SEQ ID NO:

133).

15. The antibody of claim 10, wherein substitution of alanine with threonine at position 5 of the ECD of human CD40 (SEQ ID NO:

133) reduces binding of the antibody by at least 30% relative to binding to the ECD of human CD40 (SEQ ID NO;

     133).

16. The antibody claim 10, wherein the antibody exhibits a synergistic effect when combined with CD40L.

17. The antibody of claim 1, wherein the antibody binds to one or more residues within amino acid residues 13-15 and 33-36 of the ECD of human CD40 (SEQ ID NO:

133).

18. The antibody of claim 17, which binds to one or more amino acids selected from the group consisting of amino acids 33, 34 and 36 of the ECD of human CD40 (SEQ ID NO:

133).

22. A molecular conjugate comprising the antibody of claim 1, linked to an antigen.

23. A bispecific molecule comprising the antibody of claim 1 linked to a second molecule having a binding specificity which is different from the antibody.

2. An isolated antibody which binds to human CD40 and comprises heavy and light chain variable regions, wherein the heavy and light chain variable regions respectively comprise an amino acid sequence which is at least 80% identical to:

(a) SEQ ID NOs;

3 and 4;

(b) SEQ ID NOs;

17 and 18;

(c) SEQ ID NOs;

31 and 32;

(d) SEQ ID NOs;

45 and 46;

(e) SEQ ID NOs;

59 and 60;

(f) SEQ ID NO;

73 and 74;

(g) SEQ ID NO;

87 and 88;

or

(h) SEQ ID NO;

101 and 102.

3. An isolated antibody which binds to human CD40 and comprises heavy and/or light chain variable regions having the amino acid sequence as set forth in:

(a) SEQ ID NOs;

3 and/or 4;

(b) SEQ ID NOs;

17 and/or 18;

(c) SEQ ID NOs;

31 and/or 32;

(d) SEQ ID NOs;

45 and/or 46;

(e) SEQ ID NOs;

59 and/or 60;

(f) SEQ ID NO;

73 and/or 74;

(g) SEQ ID NO;

87 and/or 88;

or

(h) SEQ ID NO;

101 and/or 102.

5. The antibody of claim 3, wherein the antibody comprises heavy and light chain variable regions having the amino acid sequence set forth in SEQ ID NOs:

17 and 18, respectively.

6. The antibody of claim 5, wherein the antibody comprises heavy and light chains having the amino acid sequence set forth in SEQ ID NOs:

135 and 136, respectively.

8. An isolated antibody which binds to the same epitope on human CD40 as an antibody comprising the heavy and light chain variable regions as set forth in claim 3.

9. An isolated antibody which competes for binding to human CD40 with an antibody comprising the heavy and light chain variable regions as set forth in claim 3.

4. An isolated antibody which binds to human CD40 and comprises the CDR sequences from the heavy and light chain variable regions respectively having the amino acid sequences set forth in:

(a) SEQ ID NOs;

3 and 4;

(b) SEQ ID NOs;

17 and 18;

(c) SEQ ID NOs;

31 and 32;

(d) SEQ ID NOs;

45 and 46;

(e) SEQ ID NOs;

59 and 60;

(f) SEQ ID NO;

73 and 74;

(g) SEQ ID NO;

87 and 88;

or

(h) SEQ ID NO;

101 and 102.

7. The antibody of claim 4, wherein the antibody comprises:

(a) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs;

5, 7, 9, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs;

11, 13, 15, respectively;

(b) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs;

19, 21, 23, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs;

25, 27, 29, respectively;

(c) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs;

33, 35, 37, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs;

39, 41, 43, respectively;

(d) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs;

47, 49, 51, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs;

53, 55, 57, respectively;

(e) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs;

61, 63, 65, respectively and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs;

67, 69, 71, respectively;

(f) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs;

75, 77, 79, respectively and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs;

81, 83, 85, respectively;

(g) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs;

89, 91, 93, respectively and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs;

95, 97, 99, respectively;

or

(h) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs;

103, 105, 107, respectively and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs;

109, 111, 113, respectively.

19. The antibody of claim 7, wherein the antibody is a human antibody.

20. The antibody of claim 7, wherein the antibody comprises a human constant region.

21. The antibody of claim 7, wherein the antibody is an antigen binding fragment, a Fab, Fab′

, (Fab′

)2, Fv, or scFv fragment.

24. A composition comprising the antibody of claim 7 and a carrier.

25. The composition of claim 24, further comprising an adjuvant.

26. The composition of claim 24, further comprising one or more other antibodies.

27. The composition of claim 26, wherein the one or more other antibodies bind to CTLA-4, PD-1, PD-L1, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin 1, TIGIT, CD113, GPR56, VISTA, B7-H3, B7-H4, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, TIM-4, B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, CD70, CD27, DR3 or CD28H.