Antibody peptide conjugates that have agonist activity at both the glucagon and glucagon-like peptide 1 receptors

An antibody peptide conjugate comprising an antibody having a light chain having the amino acid sequence of SEQ ID NO:64 and a heavy chain having the amino acid sequence of SEQ ID NO:65 conjugated to a peptide having the amino acid sequence

• (SEQ ID NO:
• 63)
• His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-
• Xaa10-Ser-Xaa12-Tyr-Leu-Asp-Xaa16-Arg-
• Ala-Ala-Xaa20-Asp-Phe-Val-Xaa24-Xaa25-
• Xaa26-Xaa27-Xaa28-Xaa29-Lys-Xaa31
• wherein
• Xaa2 is α-aminoisobutyric acid (aib) or D-Ser;
• Xaa16 is aib;
• Xaa31 is Lys or Gln when Xaa10 or Xaa24 is Lys with the proviso that for any peptide only one of Xaa10, Xaa24, or Xaa31 can be Lys;
• Xaa10 is Tyr when Xaa31 is Lys, or Lys if neither Xaa24 or Xaa31 is Lys, or Tyr or Lys if Xaa24 is Lys;
• X12 is Lys or aib when Xaa31 is Lys, with the proviso that when Xaa12 is aib, then either Xaa20 or Xaa24 is aib and Xaa10, Xaa25, Xaa26, Xaa25, Xaa27, Xaa28, and Xaa29 are Tyr, Trp, Leu, Met, Asp, and Thr, respectively;
• Xaa20 is Gln or aib when Xaa24 or Xaa31 is Lys with the proviso that when Xaa20 is aib then Xaa10, Xaa24, Xaa25, Xaa26, Xaa25, Xaa27, Xaa28, and Xaa29 are Tyr, Gln, Trp, Leu, Met, Asp, and Thr, respectively;
• Xaa24 is Gln when Xaa10 is Lys, or Gln or aib when Xaa31 is Lys, or Lys when Xaa10 and Xaa31 are Tyr and Gln, respectively, or Glu when Xaa28 is Lys, with the proviso that when Xaa24 is aib then Xaa10, Xaa25, Xaa26, Xaa27, Xaa28, an Xaa29 are Tyr, Trp, Leu, Met, Asp, and Thr, respectively;
• Xaa25 is Trp, Gln, Asp, Lys, aib, alpha-methylphenylanine, (αMePhe), alpha-methyl-leucine (αMeLeu), alpha-methyltryptophan (αMeTrp), beta-homo tryptophan (ßhoTrp), 5-hydroxy tryptophane (W(5OH)), ß-3-benzothienyl)-alanine (Bzt), 7-azatryptophan (AzTrp), 2-naphthylalanine (2Nap), (3-Pyridyl)alanine (3Pyr), 3-(2-quinoyl)-alanine (3Qui), 4,4′-biphenylalanine (BIP), or N-methyl-tryptophane (Trp(Me)) with the proviso that when Xaa25 is Gln, Asp, Lys, aib, αMePhe, αMeLeu, αMeTrp, ßhoTrp, W(5OH), Bzt, AzTrp, 2Nap, 3Pyr, 3-(2-quinoyl)-alanine (3Qui), 4,4′-biphenylalanine (BIP), or N-methyl-tryptophane (Trp(Me)), then Xaa12, Xaa20, Xaa24, Xaa26, and Xaa27 are Lys, Gln, Gln, Leu, and Met, respectively, and Xaa31 is Lys;
• Xaa26 is Leu, aib, or hexafluoroleucine (HFL) with the proviso that when Xaa26 is aib or HFL, then Xaa31 is Lys and Xaa12, Xaa20, Xaa24, Xaa25, and Xaa27 are Lys, Gln, Gln, Trp, and Met, respectively
• Xaa27 is Met, methionine sulfoxide (M(O)), homoleucine (hLeu), or homocycloexylalanine (hCha) with the proviso that when Xaa27 is M(O), hLeu, or hCha, then Xaa31 is Lys and Xaa12, Xaa20, Xaa24, Xaa25, Xaa26, Xaa28, Xaa29 are Lys, Gln, Gln, Trp, Leu, Asp, and Thr, respectively;
• Xaa28 is Asp or aib, or Lys when Xaa24 is Glu, with the proviso that when Xaa28 includes aib then Xaa24 is Lys and Xaa10, Xaa12, Xaa25, Xaa26, Xaa27, Xaa29 are Tyr, Lys, Trp, Leu, Met, and Thr, respectively;
• Xaa29 is Thr or aib with the proviso that when Xaa29 is aib then Xaa31 is Lys and Xaa10, Xaa12, Xaa25, Xaa26, Xaa27, Xaa28 are Tyr, Lys, Trp, Leu, Met, Asp, and Thr, respectively;
• one of Lys10, Lys24, or Lys31 is covalently linked at its epsilon amino group to an aminooxy acid residue;
• optionally, Lys10 may be covalently linked at its epsilon amino group to a fatty acid if Lys24 is covalently linked to aminooxy acid residue;
• wherein either the light chain includes a substitution of the amino acid at position 125 or 142 with a para-acetylphenylalanine (pAcF) or the heavy chain includes a substitution of the amino acid a position 16, 32, 33, 56, 114, 179, 198, or 211 with a AcF;
• and
• wherein the aminooxy acid residue of the peptide is covelantly linked to the pAcF residue of the antibody.