Covalent heterobivalent antibody inhibitors and ligands

An antibody inhibitor of Formula III:

• wherein
• TM is a targeting moiety for an antigen binding site (ABS) wherein the targeting moiety comprises a) an Ara h 2 allergen protein epitope ERDPYSPSQDPYSPS (SEQ ID NO:
• 6), b) a peptide WPRWLEN (SEQ ID NO:
• 1) or LLGPYELWELSH (SEQ ID NO:
• 2), or c) a penicillin G hapten, each which have a selective electrostatic affinity for the ABS of an immunoglobulin;
• TL is a targeting ligand for a conserved nucleotide binding site (NBS) of the immunoglobulin wherein the targeting ligand comprises indole-3-butyric acid (IBA) or 2-napthaleneacetic acid (NAA) and IBA or NAA has a selective electrostatic affinity for the NBS located proximal to the ABS and between the heavy chain and light chain of the immunoglobulin;
• FG is a reactive functional group capable of forming a site-directed covalent bond to the amine moiety of a lysine proximal to the NBS of an allergen reactive immunoglobulin;
• EG1 is a variable length spacer comprising one or more spacers of the formula —(CH2—X—CH2CH2—X—CH2)y— wherein the —(CH2—X—CH2CH2—X—CH2)y— spacer is linked to one or more K1 spacers;
• y is 1 to 12;
• X is O or NR wherein R is H or (C1-C4) alkyl;
• K1 is a spacer comprising one or more lysine moieties;
• EG2 is an optional variable length spacer comprising the formula —(CH2—X—CH2CH2—X—CH2)y—;
• K2 is an optional spacer comprising a lysine moiety;
• wherein the spacers EG1, EG2, K1, K2, and —(CH2—X—CH2CH2—X—CH2)y— are linked by one or more amide bonds;
• and
• TG is an optional tag comprising a chromophore or a fluorophore;
• wherein the ABS targeting moiety (TM), the NBS targeting ligand (TL), and the reactive functional group (FG) are conjugated to K1, EG1 and EG2, and TM is further conjugated to an optional tag (TG) by K2 and EG2, wherein when the antibody inhibitor bivalently binds to both the ABS and the NB S, the effective concentration of the reactive functional group (FG) near the amino acid of the immunoglobulin increases to irreversibly inhibit the immunoglobulin by the site-directed covalent bond formed by the inhibitor, and the irreversibly inhibited immunoglobulin is tagged by the chromophore or the fluorophore when the inhibitor contains TG.