IP Library › Granted Patent US 12,234,281
Granted Patent B2
US 12,234,281 · App. 17/532,292 · Granted Feb 25, 2025

Antibody-based therapy of transthyretin (TTR) amyloidosis and human-derived antibodies therefor

Inventors: Jan Grimm (Dübendorf, CH); Aubin Michalon (Baden, CH)
Assignee: Neurimmune Holding AG
C07K16/18G01N33/6896A61K2039/505C07K2317/21C07K2317/33C07K2317/34C07K2317/52C07K2317/565C07K2317/92G01N2800/28G01N2800/7047
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,234,281
App. No.
17/532,292
Granted
Feb 25, 2025
Kind
B2
Abstract

Provided are novel human-derived antibodies specific for transthyretin (TTR), preferably capable of binding misfolded, misassembled, and/or aggregated TTR species, as well as methods related thereto. In addition, methods of diagnosing and/or monitoring diseases and treatments thereof which are associated with TTR amyloidosis are provided. Assays and kits related to antibodies specific for TTR or TTR deposits and aggregates are also disclosed. The novel anti-TTR antibodies can be used in pharmaceutical and diagnostic compositions for TTR targeted immunotherapy and diagnostics.

Claims (21)

1. A recombinant anti-transthyretin (TTR) antibody that binds mutated, misfolded, misassembled, and/or aggregated TTR species and/or fragments thereof and does not recognize physiological TTR species, wherein the antibody comprises a human fragment crystallizable (Fc) region of an IgG1 isotype and comprises complementarity determining regions (CDRs), wherein:

(i) CDR-H1 comprises the amino acid sequence of SEQ ID NO: 104;

(ii) CDR-H2 comprises the amino acid sequence of SEQ ID NO: 105;

(iii) CDR-H3 comprises the amino acid sequence of SEQ ID NO: 106;

(iv) CDR-L1 comprises the amino acid sequence of SEQ ID NO: 107;

(v) CDR-L2 comprises the amino acid sequence of SEQ ID NO: 108; and

(vi) CDR-L3 comprises the amino acid sequence of SEQ ID NO: 109.

2. The antibody of claim 1 , wherein the antibody binds a TTR epitope comprising SEQ ID NO: 51.

3. The antibody of claim 2 , wherein the antibody binds the TTR epitope comprising the amino acid sequence of SEQ ID NO: 51.

4. The antibody of claim 1 , wherein the antibody:

(i) comprises a detectable label, wherein the detectable label is selected from the group consisting of an enzyme, a radioisotope, a fluorophore and a heavy metal; and/or

(ii) is attached to a drug.

5. A composition comprising the antibody of claim 1 , wherein the composition is a pharmaceutical composition and further comprises a pharmaceutically acceptable carrier.

6. A kit comprising the antibody of claim 1 and instructions for use.

7. The antibody of claim 1 , wherein the antibody comprises a heavy chain variable (VH) region comprising an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 10 and a light chain variable region (VL) region comprising an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 12.

8. The antibody of claim 1 , wherein the antibody comprises a VH region comprising the amino acid sequence set forth in SEQ ID NO: 53.

9. The antibody of claim 1 , wherein the antibody comprises a VH region comprising the amino acid sequence set forth in SEQ ID NO: 53 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 12.

10. A composition comprising the antibody of claim 1 , wherein the composition is a diagnostic composition.

11. A kit comprising the composition of claim 5 and instructions for use.

12. A kit comprising the composition of claim 10 instructions for use.

13. The composition of claim 5 , wherein the composition is a vaccine and/or comprises an additional agent for treating diseases associated with TTR amyloidosis.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 24, 2022
From: GRIMM, JAN; MICHALON, AUBIN
To: NEURIMMUNE HOLDING AG
Reel/Frame 059390/0166 →
Priority Claims (1)
EP 13199251 · Dec 20, 2013 · regional
Continuity (3)
Division 16413335 · May 15, 2019
Division 15106176
Related Publication 20220144928A1 · May 12, 2022
References Cited (37)
US 10344080B2 · Grimm et al. · 2019 [cited by applicant]
US 11180545B2 · Grimm et al. · 2021 [cited by applicant]
US 20080131907A1 · Wang et al. · 2008 [cited by applicant]
US 20160347832A1 · Hosoi et al. · 2016 [cited by applicant]
US 20160355576A1 · Grimm et al. · 2016 [cited by applicant]
US 20190345237A1 · Grimm et al. · 2019 [cited by applicant]
CN 102016059A · 2011 [cited by applicant]
JP 2010195710A · 2010 [cited by applicant]
WO WO2008081008A1 · 2008 [cited by applicant]
WO WO2009007958A2 · 2009 [cited by applicant]
WO WO2009079585A2 · 2009 [cited by applicant]
WO WO2009086539A2 · 2009 [cited by applicant]
WO WO2010030203A1 · 2010 [cited by applicant]
WO WO2010040209A1 · 2010 [cited by applicant]
WO WO2014124334A2 · 2014 [cited by applicant]
WO WO2015115331A1 · 2015 [cited by applicant]
Ando et al., “Presence of autoantibody against ATTR Val30Met after sequential liver transplantation,” Transplantation 73(5):751-755 (2002) (9 pages). [cited by applicant]
Ando, Y., “Liver Transplantation and Development of New Therapeutic Approaches for Familia Amyloidotic Polyneuropathy (FAP),” Annual Review, Shinkei 2011, Chugaiigakusha, 2011, 310-317 (English translation) (10 pages). [cited by applicant]
Bergstrom et al., “Surface exposed epitopes and structural heterogeneity of in vivo formed transthyretin amyloid fibrils,” Biochem. Biophys. Res. Commun. 348:532-539 (2006). [cited by applicant]
Chen et al., Enhancement and destruction of antibody function by somatic mutation: unequal occurrence is controlled by V gene combinatorial associations, The EMBO Journal 14(12):2784-2794 (1995). [cited by applicant]
Edwards et al., “The remarkable flexibility of the human antibody repertoire; isolation of over one thousand different antibodies to a single protein, BLyS,” J. Mol. Biol. 334(1):103-118 (2003). [cited by applicant]
English translation of JP-2010-195710 (2010) (14 pages). [cited by applicant]
English translation of Notice of Reasons for Refusal dated Oct. 2, 2018 for Japanese Patent Application No. 2016-541159 (11 pages). [cited by applicant]
Goldsteins et al., “Exposure of cryptic epitopes on transthyretin only in amyloid and in amyloidogenic mutants,” Proc. Natl. Acad. Sci. U.S.A. 96:3108-3113 (1999). [cited by applicant]
International Preliminary Report on Patentability for International Patent Application No. PCT/EP2014/079094, dated Jun. 30, 2016 (8 pages). [cited by applicant]
International Search Report for International Patent Application No. PCT/EP2014/079094, dated Apr. 28, 2014 (4 pages). [cited by applicant]
Kussie et al., “A Single Engineered Amino Acid Substitution Changes Antibody Fine Specificity,” J. Immunol. 152(1):146-152 (1994). [cited by applicant]
Lippow et al., “Computational Design of Antibody-Affinity Improvement Beyond in Vivo Maturation,” available in PMC Jan. 7, 2010, published in final edited form as: Nat. Biotechnol. 25(10):1171-1176 (2007) (14 pages). [cited by applicant]
Michalon et al., “Characterization of conformation-specific, human-derived monoclonal antibodies against TTR aggregates with potential for diagnostic and therapeutic use,” Orphanet. J. Rare Diseases 10(Suppl 1):39 (2015… [cited by applicant]
Obayashi et al., “Impact of antibodies against amyloidogenic transthyretin (ATTR) on phenotypes of patients with familial amyloidotic polyneuropathy (FAP) ATTR Valine30Methionine,” Clin. Chim. Acta. 419:127-131 (2013). [cited by applicant]
Rajpal et al., “A General Method for Greatly Improving the Affinity of Antibodies by Using Combinatorial Libraries,” Proc. Natl. Acad. Sci. U.S.A. 102(24):8466-8471 (2005). [cited by applicant]
Rudikoff et al., “Single amino acid substitution altering antigen-binding specificity,” Proc. Natl. Acad. Sci. U.S.A. 79:1979-1983 (1982). [cited by applicant]
Suhr et al., “One mutation, two distinct disease variants: unravelling the impact of transthyretin amyloid fibril composition,” J. Intern. Med. 281:337-347 (2017). [cited by applicant]
Terazaki et al., “Immunization in familiar amyloidotic polyneuropathy: counteracting deposition by immunization with a Y78F TTR mutant,” Lab Invest. 86(1):23-31 (2006). [cited by applicant]
USCAFC “ [cited by applicant]
Vajdos et al., “Comprehensive Functional Maps of the Antigen-Binding Site of an anti-ErbB2 Antibody Obtained with Shotgun Scanning Mutagenesis,” J. Mol. Biol. 320(2):415-428 (2002). [cited by applicant]
Gerasimova et al. “Protein Misfolding during Pregnancy: New Approaches to Preeclampsia Diagnostics,” Int J Mol Sci. 20(24): 1-18 (Dec. 2019). [cited by applicant]