Immunoglobulin variants

Abstract

The present invention describes IgE antagonists (including variant anti-IgE antibodies) and their use in diagnosis, therapy or prophylaxis of allergic and other IgE-mediated disorders, including asthma, food allergies, hypersensitivity and anaphylactic reactions.

1 . A polypeptide which is capable of binding to one of FCEL or FCEH but which is substantially incapable of binding to the other of FCEL or FCEH.  
     
     
         2 . The polypeptide of  claim 1  which comprises amino acid sequence which is substantially homologous to an Fcε3-Fcε4 sequence.  
     
     
         3 . The polypeptide of  claim 2  which comprises amino acid sequence greater than about 80% homologous with an Fcε3-Fcε4 sequence and which contains at least about 50 residues.  
     
     
         4 . The polypeptide of  claim 1  which is an immunoglobulin.  
     
     
         5 . The immunoglobulin of  claim 4  which is capable of binding to FCEL but which is substantially incapable of binding to FCEH.  
     
     
         6 . The immunoglobulin of  claim 5  which is an IgE analogue having a variant amino acid sequence within about residues 420 to 428, inclusive.  
     
     
         7 . The immunoglobulin of  claim 5  which is an IgE analogue having a variant amino acid sequence within about residues 446 to 453, inclusive.  
     
     
         8 . The immunoglobulin of  claim 6  further comprising IgE residues about from 373-390 and wherein the variant amino acid sequence is a deletion of one of residues 423-428.  
     
     
         9 . The immunoglobulin of  claim 4  which further comprises a cytotoxic polypeptide, an enzyme, a diagnostic label, or an immunoglobulin variable domain capable of binding a predetermined antigen.  
     
     
         10 . The immunoglobulin of  claim 5  which is an IgE analogue having a variant amino acid sequence within about residues 420-428, inclusive, and within about residues 446 to 453, inclusive.  
     
     
         11 . The immunoglobulin of  claim 10  which is capable of binding complement.  
     
     
         12 . The immunoglobulin of  claim 9  wherein the antigen is CD8 or CD3.  
     
     
         13 . The immunoglobulin of  claim 9  wherein the antigen is a lymphoid cell surface antigen.  
     
     
         14 . An immunoglobulin of  claim 9  which comprises an IgG, IgA, IgD or IgM sequence.  
     
     
         15 . A method for treating an allergic disorder which comprises administering to a patient susceptible to an allergy a therapeutically effective amount of an FCEL or FCEH specific polypeptide, provided that the FCEH-specific polypeptide is incapable of crosslinking FCEH and inducing histamine release.  
     
     
         16 . A polypeptide capable of binding to FCEL and having a human IgE beta strand D sequence which is substantially incapable of binding to FCEH, said polypeptide containing no more than about 40 residues.  
     
     
         17 . The polypeptide of  claim 16  having no more than about 30 residues.  
     
     
         18 . The polypeptide of  claim 17  wherein a residue within the beta strand D domain has been deleted or substituted, or another residue inserted within the beta strand D domain.  
     
     
         19 . A polypeptide capable of binding to FCEH, containing a beta strand D sequence of IgE, and having no more than 19 residues.  
     
     
         20 . The polypeptide of  claim 1  which is capable of binding to FCEH but not FCEL and comprises IgE sequence selected from about residues 420 to about 442.  
     
     
         21 . The polypeptide of  claim 19  which comprises the IgE amino acid sequence of residues K423-R428.  
     
     
         22 . The polypeptide of  claim 1  which comprises less than about 20 residues and which is conformationally constrained.  
     
     
         23 . The polypeptide of  claim 1  which binds FCEL with at least about 75% of the affinity of native IgE and binds FCEH with no greater than about 10% of the affinity of native IgE.  
     
     
         24 . The immunoglobulin of  claim 4  which comprises an IgE complementarity determining region.  
     
     
         25 . The immunoglobulin of  claim 4  which is capable of binding to FCEH but which is substantially incapable of binding to FCEL.  
     
     
         26 . The immunoglobulin of  claim 25  which is an IgE analogue having a variant amino acid sequence within about residues 373 to 390, inclusive or residues 446 to 453, inclusive.  
     
     
         27 . The immunoglobulin of  claim 25  which is an IgE analogue having a variant amino acid sequence within about residues 382 to 390, inclusive or residues 446 to 453, inclusive.  
     
     
         28 . The immunoglobulin of  claim 27  which further comprises a FCEH-binding loop EF and beta strand D domain.  
     
     
         29 . The immunoglobulin of  claim 24  which further comprises an immunoglobulin variable domain capable of binding a predetermined antigen, an enzyme or a diagnostic label.  
     
     
         30 . The immunoglobulin of  claim 29  wherein the antigen is CD8 or CD3.  
     
     
         31 . The immunoglobulin of  claim 29  wherein the antigen is a lymphoid cell surface antigen.  
     
     
         32 . The immunoglobulin of  claim 25  which comprises an IgG, IgA, IgD or IgM sequence.  
     
     
         33 . The immunoglobulin of  claim 25  which binds FCEH with at least about 75% of the affinity of native IgE, and binds FCEL with no greater than about 10% of the efficiency of native IgE.  
     
     
         34 . A polypeptide capable of binding to FCEL and comprising a FCEL binding domain of the human loop AB-beta strand B of IgE, said polypeptide having no more than about 25 residues.  
     
     
         35 . The polypeptide of  claim 34  which is human.  
     
     
         36 . The polypeptide of  claim 34  having no more than about 10 residues.  
     
     
         37 . The polypeptide of  claim 34  which is not A358-T389 or R383-I388.  
     
     
         38 . The polypeptide of  claim 34  wherein beta strand D is deleted.  
     
     
         39 . The polypeptide of  claim 37  wherein the amino acid sequence comprises the IgE sequence I382-T389.  
     
     
         40 . An antibody which is capable of binding to FCEL-bound IgE but is substantially incapable of binding to FCEH-bound IgE, comprising a human Kabat CDR domain into which has been substituted an analogous residue from a Kabat CDR domain of MAE1, MAE13, MAE15, MAE17.  
     
     
         41 . The antibody of  claim 40  wherein the residue is from the MAE11, MAE13 or MAE15 Kabat VH1 CDR domain.  
     
     
         42 . The antibody of  claim 40  wherein the substituted amino acid sequence comprises from 1 to about 7 residues from a MAE11, MAE13 or MAE15 Kabat CDR domain  
     
     
         43 . The antibody of  claim 40  wherein the substituted residue is from the MAE11, MAE13 or MAE15 Kabat VH1, VH2, VH3, VL1, VL2 and VL3 domains.  
     
     
         44 . The antibody of  claim 40  which comprises non-CDR sequence from a Kabat human consensus antibody.  
     
     
         45 . The antibody of  claim 44  wherein the consensus antibody is Kabat subgroup III for heavy chain and kappa subgroup I for light chain.  
     
     
         46 . The antibody of  claim 40  further comprising a residue substituted from a MAE11, MAE13, MAE15 or MAE17 framework or VH-VL interface domain into the analogous residue of the human antibody.  
     
     
         47 . The antibody of  claim 40  wherein the residue is from the heavy chain framework.  
     
     
         48 . The antibody of  claim 47  wherein the residue is VH78, VH60 or VH61.  
     
     
         49 . An antibody which is capable of binding to FCEL-bound IgE but is substantially incapable of binding to FCEH-bound IgE, comprising the heavy and light chain sequences of humae11ver. 1, 2, 3, 4, 5, 6, 7, 7a, 8, 8a, 8b or 9.  
     
     
         50 . The antibody of  claim 48  which is humae11ver. 9.  
     
     
         51 . A bispecific antibody which is capable of binding to FCEL-bound IgE but is substantially incapable of binding to FCEH-bound IgE.  
     
     
         52 . An antibody which is (a) monovalent for FCEL-bound IgE but is substantially incapable of binding to FCEH-bound IgE and (b) is capable of an immunoglobulin effector function and comprises an Fc domain containing at least two heavy chains.  
     
     
         53 . An antibody which is capable of binding to FCEL-bound IgE but is substantially incapable of binding to FCEH-bound IgE, comprising a human consensus heavy chain and light chain sequence.  
     
     
         54 . The antibody of  claim 52  wherein the consensus heavy chain is Kabat subgroup III and the consensus light chain is Kabat kappa subgroup I.  
     
     
         55 . An antibody which is capable of binding to FCEL-bound IgE but is substantially incapable of binding to FCEH-bound IgE, comprising a human heavy chain and light chain sequence, and which has an IgE affinity which is substantially the same as or greater than that of MAE11 for IgE.  
     
     
         56 . The antibody of  claim 54  wherein the affinity for IgE is about 0.1 to 100 times greater than that of MAE11 for IgE.  
     
     
         57 . The antibody of  claim 54  wherein the human heavy chain or light chain sequence comprises a residue substituted from MAE11, MAE13 or MAE15.