Anti-cd40 binding molecules having engineered fc domains and therapeutic uses thereof

Abstract

The disclosure provides CD40-binding molecules comprising engineered human IgG domains, for example, human IgG1, IgG2, and IgG4 variants having mutations in the hinge domain, which exhibit altered binding activity to one or more Fcγ receptors. Also described herein are methods for selectively activating or inhibiting immune responses in a subject using the CD40-binding molecules.

1 - 68 . (canceled) 
     
     
         69 . An anti-CD40 antibody, comprising (a) a heavy chain that comprises a heavy chain variable (V H ) region, and (b) a light chain that comprises a light chain variable (V L ) region;
 wherein the V H  region comprises the same heavy chain complementary determining regions (CDRs) and the same light chain CDRs as antibody 383, which comprises a V H  of SEQ ID NO:128 and a V L  of SEQ ID NO:129; and   wherein the heavy chain further comprises an engineered Fc region, which comprises at least one mutation at any of positions 228-329 as compared to a wild-type Fc region counterpart, wherein the numbering is according to the EU index, and wherein the Fc region is of an IgG1 or IgG4.   
     
     
         70 . The anti-CD40 antibody of  claim 69 , wherein the V H  region comprises the amino acid sequence of SEQ ID NO:128. 
     
     
         71 . The anti-CD40 antibody of  claim 69 , wherein the V L  region comprises the amino acid sequence of SEQ ID NO:129. 
     
     
         72 . The anti-CD40 antibody of  claim 69 , wherein the V H  region comprises the amino acid sequence of SEQ ID NO:128 and the V L  region comprises the amino acid sequence of SEQ ID NO:129. 
     
     
         73 . The anti-CD40 antibody of  claim 69 , wherein the antibody is a human antibody or a humanized antibody. 
     
     
         74 . The anti-CD40 antibody of  claim 69 , wherein the engineered Fc region is of an IgG1 and comprises:
 (a) an amino acid substitution or deletion within positions 233-238;   (b) a substitution at one or more of positions 265, 267, 297, 328, and 329; or   (c) a combination of (a) and (b).   
     
     
         75 . The anti-CD40 antibody of  claim 74 , wherein the engineered Fc region comprises a deletion at one or more of positions 236-238. 
     
     
         76 . The anti-CD40 antibody of  claim 75 , wherein the engineered Fc region further comprises a substitution at one or more of positions 233-235, 267, 273, 327, and 328. 
     
     
         77 . The anti-CD40 antibody of  claim 74 , wherein the engineered Fc region is G1m2, G1m15, G1m17, G1m18, G1m19, G1m25, G1m27, G1m28, G1m29, or G1m240. 
     
     
         78 . The anti-CD40 antibody of  claim 69 , wherein the engineered Fc region is of an IgG4 and comprises:
 (a) an amino acid substitution or deletion within positions 235-238;   (b) a substitution at one or more of positions 228, 265, 267, 273, 297, and 328; or   (c) a combination of (a) and (b).   
     
     
         79 . The anti-CD40 antibody of  claim 78 , wherein the engineered Fc region comprises S228P substitution and a substitution or deletion at one or more of positions 235-238. 
     
     
         80 . The anti-CD40 antibody of  claim 78 , wherein the engineered Fc region is selected from the group consisting of G4m2, G4m20, G4m28, G4m30, G4m41, G4m42, G4m46, G4mPE, G4mAA, and G4m40. 
     
     
         81 . A pharmaceutical composition, comprising the anti-CD40 antibody of  claim 69  and a pharmaceutically acceptable carrier. 
     
     
         82 . A method for modulating an immune response in a subject, the method comprising administering to a subject in need thereof the pharmaceutical composition of  claim 81 . 
     
     
         83 . The method of  claim 82 , wherein the subject is a human patient having or suspected of having cancer. 
     
     
         84 . The method of  claim 83 , wherein the pharmaceutical composition is administered to the subject by intravenous infusion. 
     
     
         85 . The method of  claim 83 , further comprising administering to the subject an effective amount of an immunomodulatory agent, a chemotherapeutic agent, or a combination thereof. 
     
     
         86 . The method of  claim 85 , wherein the immunomodulatory agent is a therapeutic vaccine, or a checkpoint inhibitor. 
     
     
         87 . The method of  claim 83 , further comprising administering to the subject an effective amount of a checkpoint inhibitor, a chemotherapeutic agent, or a combination thereof. 
     
     
         88 . The method of  claim 87 , wherein the checkpoint inhibitor is a PD1 inhibitor.