US2021147538A1PendingUtilityA1

Agonistic antibodies that bind cd40

Assignee: CELLDEX THERAPEUTICS INCPriority: Apr 18, 2016Filed: Jan 8, 2021Published: May 20, 2021

Est. expiryApr 18, 2036(~9.8 yrs left)· nominal 20-yr term from priority

Inventors:Tibor Keler Joel Goldstein Laura A. Vitale Lizhen He Tom O'Neill Andrea Crocker Karuna Sundarapandiyan Lawrence J. Thomas Jenifer Widger

A61K 39/39541C07K 16/2803C07K 2317/92A61K 2039/505C07K 2317/73A61P 37/04C07K 14/54C07K 16/2878C07K 2317/74C07K 2317/75C07K 14/715C07K 2317/21A61P 35/00C07K 2317/34A61K 39/385C07K 14/70575A61P 35/02A61K 45/06A61K 38/177A61K 2300/00

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References

Claims

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

exact text as granted — not AI-modified

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.   
     
     
         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.   
     
     
         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.   
     
     
         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. 
     
     
         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.   
     
     
         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 . 
     
     
         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). 
     
     
         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. 
     
     
         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. 
     
     
         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. 
     
     
         28 . A method for inducing or enhancing an immune response against an antigen in a subject comprising administering to the subject the antibody, molecular conjugate, composition or bispecific molecule of any one of  claims 1 - 26  in an amount effective to induce or enhance an immune response against an antigen. 
     
     
         29 . The method of  claim 28 , further comprising the step of administering the antigen. 
     
     
         30 . The method of  claim 29 , wherein the antigen is administered simultaneously, separately or sequentially from the antibody, composition, or bispecific molecule. 
     
     
         31 . A method of inhibiting growth of CD40 expressing cells comprising contacting the cells with the antibody, composition or bispecific molecule of any one of  claims 1 - 26 , in an amount effective to inhibit growth of CD40 expressing cells. 
     
     
         32 . A method for treating a disorder in a subject comprising administering to the subject the antibody, composition or bispecific molecule of any one of  claims 1 - 26  in an amount effective to treat the disorder. 
     
     
         33 . The method of  claim 32 , wherein the disorder is a cancer selected from the group consisting of chronic lymphocytic leukemia, mantle cell lymphoma, primary central nervous system lymphoma, Burkitt&#39;s lymphoma and marginal zone B cell lymphoma. 
     
     
         34 . The method of any one of  claims 28 - 33 , wherein the antibody does not block the binding of CD40L to human CD40. 
     
     
         35 . The method of any one of  claims 28 - 34 , further comprising administering one or more therapeutic agents to the subject. 
     
     
         36 . The method of  claim 35 , wherein the therapeutic agent is another antibody. 
     
     
         37 . The method of  claim 36 , wherein the antibody is an anti-PD-1 antibody, an anti-PD-L1, and/or an anti-CTLA-4 antibody. 
     
     
         38 . The method of  claim 37 , wherein the first and second antibodies are administered concurrently. 
     
     
         39 . The method of  claim 37 , wherein the first and second antibodies are administered sequentially.

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