Antigen binding complex having agonistic activity and methods of use

Abstract

Provided herein are antigen binding polypeptides and complexes thereof having agonist activity. Also provided are methods for screening for complexes or polypeptides having agonist activity, enhancing the agonist activity of a polypeptide, and for agonizing a cell surface receptor using the complexes and polypeptide described herein.

1 - 155 . (canceled) 
     
     
         156 . A nucleic acid encoding a hexameric antigen binding complex having agonist activity comprising six subunits, wherein each subunit comprises at least one antigen binding polypeptide comprising at least one antigen binding region from an antibody that binds to OX40 and a modified human IgG1 Fc region that comprises amino acid substitutions E345R, E430G and S440Y, positions according to EU numbering based on native human IgG1, wherein the complex has agonist activity for OX40 bound by the complex. 
     
     
         157 - 164 . (canceled) 
     
     
         165 . The nucleic acid of  claim 156 , wherein each antigen binding polypeptide binds to the same epitope on OX40. 
     
     
         166 . The nucleic acid of  claim 156 , wherein the antigen binding region is selected from the group consisting of Fv, Fab, Fab′, F(ab′) 2 , and scFv. 
     
     
         167 . The nucleic acid of  claim 156 , wherein the Fc region further comprises a modification for diminished C1q binding and/or Complement Dependent Cytotoxicity (CDC). 
     
     
         168 . The nucleic acid of  claim 167 , wherein the modification for diminished C1q binding and/or CDC comprises a K322A amino acid substitution in the Fc region of a human IgG1 (EU numbering). 
     
     
         169 . The nucleic acid of  claim 156 , wherein the antigen binding region comprises an antigen binding region from a monospecific antibody, bispecific antibody or multispecific antibody. 
     
     
         170 . The nucleic acid of  claim 156 , wherein the complex comprises at least one subunit that comprises (a) a VH domain comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4; and/or (b) a VL domain comprising (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:7. 
     
     
         171 . The nucleic acid of  claim 170 , wherein each of the six subunits comprises (a) a VH domain comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4; and/or (b) a VL domain comprising (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:7. 
     
     
         172 . The nucleic acid of  claim 156 , wherein the complex comprises at least one subunit that comprises (a) a VH domain comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:30, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33; and/or (b) a VL domain comprising (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:39, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42. 
     
     
         173 . The nucleic acid of  claim 172 , wherein each of the six subunits comprises (a) a VH domain comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:30, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33; and/or (b) a VL domain comprising (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:39, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42. 
     
     
         174 . The nucleic acid of  claim 156 , wherein the complex comprises (a) at least a first subunit that binds a first epitope of OX40; and (b) at least a second subunit that binds a second epitope of OX40, wherein the first epitope of OX40 is different from the second epitope of OX40. 
     
     
         175 . The nucleic acid of  claim 174 , wherein the first subunit comprises (a) a VH domain comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4; and/or (b) a VL domain comprising (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:7; and
 wherein the second subunit comprises (a) a VH domain comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:30, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33; and/or (b) a VL domain comprising (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:39, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42.   
     
     
         176 . The nucleic acid of  claim 156 , wherein the antibody is a bispecific antibody that comprises (a) at least a first arm that binds a first epitope of OX40 and (b) at least a second arm that binds a second epitope of OX40, wherein the first epitope of OX40 is different from the second epitope of OX40. 
     
     
         177 . The nucleic acid of  claim 176 , wherein the first arm comprises (a) a VH domain comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4; and/or (b) a VL domain comprising (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:7; and
 wherein the second arm comprises (a) a VH domain comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:30, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33; and/or (b) a VL domain comprising (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:39, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42.   
     
     
         178 . The nucleic acid of  claim 156 , wherein the Fc region further comprises a modification for attenuating effector function. 
     
     
         179 . The nucleic acid of  claim 178 , wherein the modification for attenuating effector function does not result in a modification of the glycosylation pattern of the Fc region.