Binding molecules with modified J-chain
The present invention provides binding molecules that include an IgM, IgA, IgG/IgM or IgG/IgA antibody with a modified J-chain that includes a binding moiety that antagonizes a T-cell inhibitory signaling pathway, and their uses.
1. An antibody comprising: five IgM antibody monomers or five IgG/IgM antibody monomers that form a pentamer; and a modified J-chain, wherein the modified J-chain comprises SEQ ID NO: 1 and a binding moiety that antagonizes a T-cell inhibitory signaling pathway, wherein the binding moiety is attached to SEQ ID NO: 1 at a C- or an N-terminus of the binding moiety, wherein the binding moiety is attached to SEQ ID NO: 1 at a C- or an N-terminus of SEQ ID NO:1 or between cysteine residues 92 and 101 of SEQ ID NO: 1, wherein the IgG/IgM antibody monomers are hybrid antibody monomers which contain an IgM tail-piece at the end of the IgG heavy chain and has the ability to incorporate and form polymers with the modified J-chain, and wherein the binding moiety on the modified J-chain binds to a cell surface protein selected from the group consisting of: CTLA4, PD-1, TIM3, LAG3, BTLA, VISTA and TIGIT.
2. The antibody according to claim 1 , wherein the antibody monomers comprise antigen-binding sites that antagonize a T-cell inhibitory signaling pathway.
3. The antibody according to claim 2 , wherein the antigen-binding sites bind to a target selected from the group consisting of: PD-1, PD-L1, TIM3 and LAG3.
4. The antibody according to claim 1 , wherein the antibody monomers comprise antigen-binding sites that agonize a T-cell stimulatory signaling pathway.
5. The antibody according to claim 4 , wherein the antigen-binding sites bind to a target selected from the group consisting of: CD137, OX40, CD40, GITR, CD27 and HVEM.
6. The antibody according to claim 1 , wherein the antibody monomers comprise antigen-binding sites that bind to a target selected from the group consisting of: EGFR, HER2, HER3, EpCAM, CEACAM, Gp100, MAGE1 and PD-L1.
7. The antibody according to claim 1 , wherein the antibody monomers comprise antigen-binding sites that bind to a target selected from the group consisting of: NY-ESO-1, Sialyl Lewis X antigen and Tn antigen.
8. The antibody according to claim 1 , wherein the antibody monomers comprise antigen-binding sites that bind to a cell surface protein on a hematologic cancer cell selected from the group consisting of: CD19, CD20, CD22, CD33, CD38, CD52 and CD70.
9. The antibody according to claim 1 , wherein the J-chain binding moiety is attached to SEQ ID NO: 1 by direct or indirect fusion, wherein indirect fusion is via a peptide linker.
10. The antibody according to claim 1 , wherein the binding moiety was introduced into the native human J-chain sequence of SEQ ID NO: 1 by chemical or chemo-enzymatic derivatization.
11. The antibody according to claim 1 , wherein the binding moiety was introduced into SEQ ID NO: 1 by a cleavable or non-cleavable chemical linker.
12. The antibody according to claim 1 , wherein the binding moiety of the modified J-chain is selected from the group consisting of: antigen-binding fragments of antibodies, antibody-drug conjugates, antibody-like molecules, antigen-binding fragments of antibody-like molecules, ligands, and receptors.
13. The antibody according to claim 12 , wherein the binding moiety is an antigen-binding fragment of an antibody and is selected from the group consisting of: F(ab′) 2 , Fab′, Fab, Fv, scFv, and single domain antibody.
14. A pharmaceutical composition for the treatment of cancer, comprising an effective amount of the antibody according to claim 1 and a pharmaceutically acceptable carrier.