IP Library › Granted Patent US 12,378,323
Granted Patent B2
US 12,378,323 · App. 17/092,423 · Granted Aug 5, 2025

IgM and IgE heavy chain domain 2 as covalently linked homodimerization modules for the generation of fusion proteins with dual specificity

Inventors: Roland Kontermann (Nurtingen, DE); Oliver Seifert (Stuttgart, DE); Aline Plappert (Stuttgart, DE)
Assignee: UNIVERSITAT STUTTGART
C07K16/32A61K39/3955C07K14/435C07K14/52C07K14/525C07K16/2863C07K16/468C07K2317/24C07K2317/31C07K2317/35C07K2317/524C07K2317/622C07K2317/64C07K2317/73C07K2319/30
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Quick Facts
Patent No.
US 12,378,323
App. No.
17/092,423
Granted
Aug 5, 2025
Kind
B2
Abstract

The present invention provides a polypeptides comprising a heavy chain domain 2 (HD2) from IgM or IgE and at least one pharmaceutically active moiety, complexes thereof and their use for therapy and prophylaxis.

Claims (27)

1. A polypeptide comprising a heavy chain domain 2 (HD2) from IgM and at least one pharmaceutically active moiety, under the proviso that the pharmaceutically active moiety is not a Fab or Fc fragment from IgM or IgE, wherein the HD2 domain from IgM comprises an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 1 or a dimerizing variant thereof;

wherein the polypeptide does not comprise heavy chain constant domain CH3 of IgM;

and wherein the pharmaceutically active moiety is an antibody or antigen binding fragment thereof, a ligand, a cytokine, a receptor, or a tumor marker.

2. The polypeptide of claim 1 , wherein at least one pharmaceutically active moiety is connected to the N- and/or C-Terminus of the HD2.

3. The polypeptide of claim 1 , wherein at least one pharmaceutically active moiety is connected to the HD2 directly or indirectly via one or more linkers.

4. The polypeptide of claim 3 , wherein the one or more linkers comprise peptide linkers.

5. The polypeptide of claim 4 , wherein the peptide linkers comprise one or more cleavage sites.

6. The polypeptide of claim 1 , wherein at least two identical or at least two different pharmaceutically active moieties are connected to the HD2.

7. The polypeptide of claim 1 , wherein the ligand is selected from the group consisting of an antigen-binding molecule, a scaffold protein, a ligand-binding receptor fragment, and an aptamer.

8. The polypeptide of claim 7 , wherein the antigen-binding molecule is selected from the group consisting of an antibody fragment, a Fab fragment, a Fab′ fragment, a heavy chain antibody, a single-domain antibody (sdAb), a variable domain of a heavy chain antibody, a VHH, a Nanobody, a single-chain variable fragment (scFv), a tandem scFv, a bispecific T-cell engager, a diabody, a single-chain diabody, a triple body, a nanoantibody, a scaffold protein, and a fusion protein thereof.

9. The polypeptide of claim 1 , wherein the antibody or antigen binding fragment is an anti-HER2 or an anti-EGFR scFv.

10. The polypeptide of claim 1 , wherein the cytokine is the tumor-necrosis factor (TNF).

11. The polypeptide of claim 1 , wherein the cytokine is the TNF-relative apoptosis-inducing factor (TRAIL).

12. The polypeptide of claim 1 , which further comprises a half-life extension module, selected from the group consisting of an immunoglobulin binding domain (IgBD), albumin, an albumin-binding domain (ABD), a fatty acid, a single-domain antibody, a VHH, a scaffold protein, and a ligand exhibiting affinity for a long-circulating plasma protein.

13. The polypeptide of claim 1 , which further comprises an imaging molecule, selected from the group consisting of a bioluminescent reagent, a chemiluminescent reagent, a fluorescent imaging reagent, a photosensitizer, a chelating reagent, and a radioactive moiety.

14. A complex comprising at least two polypeptides according to claim 1 .

15. The complex of claim 14 , wherein the at least two polypeptides are connected via their HD2 domains.

16. The complex of claim 14 , wherein the at least two polypeptides are connected via covalent or non-covalent bonds.

17. The complex of claim 16 , wherein the at least two polypeptides are connected via a covalent bond and the covalent bond is a disulfide bond.

18. The complex of claim 14 , wherein the at least two polypeptides are identical or different.

19. A composition comprising the polypeptide of claim 1 and a pharmaceutically acceptable carrier.

20. The composition of claim 19 , which further comprises a pharmaceutically acceptable excipient.

21. The polypeptide of claim 1 , wherein the HD2 domain from IgM consists of the amino acid sequence according to SEQ ID NO: 1.

22. The polypeptide of claim 1 , wherein the polypeptide does not comprise heavy chain constant domain CH1 of IgM.

23. The polypeptide of claim 1 , wherein the polypeptide does not comprise heavy chain constant domain CH4 of IgM.

24. The polypeptide of claim 1 , wherein the polypeptide does not comprise heavy chain constant domain CH1 and CH4 of IgM.

25. The polypeptide of claim 12 , wherein the half-life extension module is PEGylated, HESylated, polysialylated, N-glycosylated, or O-glycosylated.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 1, 2021
From: KONTERMANN, ROLAND; SEIFERT, OLIVER; PLAPPERT, ALINE
To: UNIVERSITÄT STUTTGART
Reel/Frame 055101/0907 →
Priority Claims (1)
WO PCT/EP2012/056938 · Apr 16, 2012 · international
Continuity (3)
Continuation 15645892 · Jul 10, 2017
Continuation 14391930
Related Publication 20210139606A1 · May 13, 2021
References Cited (41)
US 7754208B2 · Ledbettter et al. · 2010 [cited by applicant]
US 8980266B2 · Eckelman et al. · 2015 [cited by applicant]
US 10301368B2 · Sahin · 2019 [cited by examiner]
US 10875928B2 · Kontermann · 2020 [cited by examiner]
US 11142558B2 · Fischer · 2021 [cited by examiner]
US 20060171942A1 · Saxon et al. · 2006 [cited by applicant]
US 20080050374A1 · Cho et al. · 2008 [cited by applicant]
US 20080227958A1 · Thompson · 2008 [cited by examiner]
US 20100233079A1 · Jakob et al. · 2010 [cited by applicant]
US 20120276099A1 · Poppe et al. · 2012 [cited by applicant]
JP S59044399 · 1984 [cited by applicant]
WO WO9203569 · 1992 [cited by applicant]
WO WO200025722 · 2000 [cited by applicant]
WO WO200047740 · 2000 [cited by applicant]
WO WO0187982 · 2001 [cited by applicant]
WO WO2002072605 · 2002 [cited by applicant]
WO WO2002088317 · 2002 [cited by applicant]
WO WO2005017148 · 2005 [cited by applicant]
WO WO2008012543 · 2008 [cited by applicant]
WO WO2008151088 · 2008 [cited by applicant]
WO WO2010010051 · 2010 [cited by applicant]
WO WO2011064257 · 2011 [cited by applicant]
Zhang et al., J Biol Chemistry 267(33): 24069-24076 (Year: 1992). [cited by examiner]
Hofmann et al., Journal of American Chemical Society 140: 167-175 (Year: 2018). [cited by examiner]
Piche-Nicholas et al., MABS 10(1): 81-94 (Year: 2018). [cited by examiner]
Colman, “Effects of amino acid sequence changes on antibody-antigen interactions.” Research in Immunology, 145(1):33-35 (Jan. 1994). [cited by applicant]
Hellman et al. “Profound reduction in alergen sensitivity following treatment with a novel allergy vaccine,” European Journal of Immunology, 24(2): 415-420 (1994). [cited by applicant]
MacCallum et al., “Antibody-antigen Interactions: Contact Analysis and Binding Site Topography” J. Mol. Biol., 262:732-745 (1996). [cited by applicant]
Rudikoff et al., “Single amino acid substitution altering antigen-binding specificity” Proc. Natl. Acad. Sci. USA, 79(6):1979-83 (Mar. 1982). [cited by applicant]
Sayers et al., “Combining proteasome inhibition with TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) for cancer therapy” Cancer Immunol Immunother 55: 76-84 (2006). [cited by applicant]
Seifert et al., “The IgM CH2 domain as covalently linked homodimerization module for the generation of fusion proteins with dual specificity,” Protein Engineering, Deign and Selection, 25(10): 603-612 (2012). [cited by applicant]
Vernersson et al., “Generation of therapeutic antibody responses against IgE through vaccination,” FASEB Journal 16(8): 875-877 (2002). [cited by applicant]
Vie et al., Human fusion proteins between interleukin 2 and IgM heavy chain are cytotoxic fore cells expressing the Interleukin 2 receptor, PNAS, 89(23): 11337-11341 (1992). [cited by applicant]
Wang et al., “Sythetic IgE peptide vaccine for immunotherapy of allergy,” Vaccine, 21(15): 1580-1590 (2003). [cited by applicant]
Wu et al., Humanization of a murine monoclonal antibody by simultaneous optimization of framework and CDR residues J. Mol. Biol. 294:151-162 (1999). [cited by applicant]
The International Search Report for International Application No. PCT/EP2013/001126, mailed Jun. 18, 2013. [cited by applicant]
Lloyd et al., Protein Engineering, Design & Selection 22:159-168 (Year: 2009). [cited by applicant]
Edwards et al., J Mol Biol 334(1):103-118 (Year: 2003). [cited by applicant]
Dorrington et al., Immunological Rev., 1978, vol. 41, p. 3-25. [cited by applicant]
Gieffers et al., Cancer Research, Apr. 15, 2012, vol. 72, No. 8, Abstract 3856. [cited by applicant]
Siegemund et al., Cell Death and Disease, 2012, vol. 3, e295, p. 1-11, published online Apr. 12, 2012. [cited by applicant]