IP Library › Granted Patent US 12,264,195
Granted Patent B2
US 12,264,195 · App. 18/660,162 · Granted Apr 1, 2025

Modified immunoglobulins for targeting amyloid deposits

Inventors: Jonathan S. Wall (Knoxville, TN); James S. Foster (Knoxville, TN); Spencer Guthrie (San Francisco, CA)
Assignees: Attralus, Inc; University of Tennessee Research Foundation
C07K16/18A61K47/6843A61P25/28C12N15/85A61K2039/505C07K2317/24C07K2317/52C07K2317/55C07K2317/565C07K2317/622C07K2317/92C07K2317/94C07K2319/00C07K2319/01
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Quick Facts
Patent No.
US 12,264,195
App. No.
18/660,162
Granted
Apr 1, 2025
Kind
B2
Abstract

Provided herein are modified immunoglobulins comprising an amyloid reactive peptide joined to an antibody, as well as humanized antibodies that bind to human amyloid fibrils and antibody-peptide fusion proteins. Also provided herein are methods of treating amyloid-based diseases by administering a modified immunoglobulin, humanized antibody, or antibody-peptide fusion protein.

Claims (72)

1. A method of treating a subject having systemic amyloidosis, comprising administering to the subject an effective amount of a modified immunoglobulin, comprising:

(i) an amyloid-reactive peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-14; and

(ii) an Ig antibody or functional fragment thereof that binds to human amyloid fibrils, wherein the Ig antibody or functional fragment thereof comprises a light chain comprising a light chain variable region (VL) and a heavy chain comprising a heavy chain variable region (VH), wherein:

a) the VL comprises a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 64-70, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO:22, and the VH comprises a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO:17, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO:18, and a CDR-H3 comprising the amino acid sequence LDY;

b) the VL comprises a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO:21, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO:22, and the VH comprises a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO:17, a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-81; and a CDR-H3 comprising the amino acid sequence LDY; or

c) the VL comprises a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 64-70, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO:22, and the VH comprises a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO:17, a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-81; and a CDR-H3 comprising the amino acid sequence LDY; and

wherein the modified immunoglobulin is a fusion protein comprising the Ig antibody or functional fragment thereof joined to the amyloid-reactive peptide.

2. The method of claim 1 , wherein the amyloid-reactive peptide comprises an amino acid sequence set forth in SEQ ID NO:1 or SEQ ID NO:2.

3. The method of claim 1 , wherein the Ig antibody or functional fragment thereof comprises human framework sequences.

4. The method of claim 1 , wherein the Ig antibody or functional fragment thereof comprises a human Fc region.

5. The method of claim 1 , wherein the Ig antibody is humanized.

6. The method of claim 1 , wherein the VL comprises one or more amino acid residues selected from the group consisting of:

a. Tyr at position 36;

b. Leu at position 37;

c. Leu at position 46;

d. Leu at position 85; and

e. Phe at position 87,

wherein the amino acid positions are numbered according to the numbering system of Kabat.

7. The method of claim 1 , wherein the systemic amyloidosis is selected from the group consisting of AL, AH, Aβ2M, ATTR, transthyretin, AA, AApoAI, AApoAII, AGel, ALys, ALEct2, AFib, or ACys.

8. The method of claim 1 , wherein the subject is a human.

9. The method of claim 1 ,

wherein the VH comprises one or more amino acid residues selected from the group consisting of:

a. Val at position 37;

b. Leu at position 48;

c. Leu at position 67;

d. Ser at position 68;

e. Lys at position 71;

f. Ser at position 76;

g. Val at position 78;

h. Leu at position 79;

i. Phe at position 80;

j. Thr at position 89;

k. Val at position 93; and

l. Thr at position 94,

wherein the amino acid positions are numbered according to the numbering system of Kabat.

10. The method of claim 9 , wherein the VL comprises Leu at position 46 and Phe at position 87, and the VH comprises Leu at position 48, Ser at position 76, Val at position 78, Leu at position 79, Phe at position 80, and Thr at position 94.

11. The method of claim 10 , wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:36 and the VH comprises the amino acid sequence set forth in SEQ ID NO:55.

12. The method of claim 11 , wherein the amyloid-reactive peptide comprises the amino acid sequence set forth in SEQ ID NO:2.

13. A method of identifying an amyloid deposit of a systemic amyloidosis in a subject, comprising:

administering a modified immunoglobulin to the subject, wherein the modified immunoglobulin comprises:

(i) an amyloid-reactive peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-14; and

(ii) an Ig antibody or functional fragment thereof that binds to human amyloid fibrils, wherein the Ig antibody or functional fragment thereof comprises a light chain comprising a light chain variable region (VL) and a heavy chain comprising a heavy chain variable region (VH), wherein:

a) the VL comprises a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 64-70, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO:22, and the VH comprises a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO:17, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO:18, and a CDR-H3 comprising the amino acid sequence LDY;

b) the VL comprises a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20; a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO:21, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO:22, and the VH comprises a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO:17, a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-81; and a CDR-H3 comprising the amino acid sequence LDY; or

c) the VL comprises a CDR-L1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 64-70, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO:22, and the VH comprises a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO:17, a CDR-H2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71-81; and a CDR-H3 comprising the amino acid sequence LDY; and

wherein the modified immunoglobulin is a fusion protein comprising the Ig antibody or functional fragment thereof joined to the amyloid-reactive peptide, and

wherein the modified immunoglobulin comprises a detectable label; and

detecting a signal from the modified immunoglobulin.

14. The method of claim 13 , wherein the VL comprises a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO:64, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO:21, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO:22, and the VH comprises a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO:17, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO:73, and a CDR-H3 comprising the amino acid sequence LDY.

15. The method of claim 13 , wherein the amyloid-reactive peptide comprises the amino acid sequence set forth in SEQ ID NO:2.

16. The method of claim 13 , wherein the Ig antibody or functional fragment thereof comprises human framework sequences.

17. The method of claim 13 , wherein the Ig antibody or functional fragment thereof comprises a human Fc region.

18. The method of claim 13 , wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:36 and the VH comprises the amino acid sequence set forth in SEQ ID NO:55.

19. The method of claim 13 , wherein the systemic amyloidosis is selected from the group consisting of AL, AH, Aβ2M, ATTR, transthyretin, AA, AApoAI, AApoAII, AGel, ALys, ALEct2, AFib, or ACys.

20. The method of claim 13 , wherein the subject is a human.

21. The method of claim 13 , wherein the VH comprises one or more amino acid residues selected from the group consisting of:

a. Val at position 37;

b. Leu at position 48;

c. Leu at position 67;

d. Ser at position 68;

e. Lys at position 71;

f. Ser at position 76;

g. Val at position 78;

h. Leu at position 79;

i. Phe at position 80;

j. Thr at position 89;

k. Val at position 93; and

l. Thr at position 94,

wherein the amino acid positions are numbered according to the numbering system of Kabat.

22. The method of claim 21 , wherein the VL comprises Leu at position 46 and Phe at position 87, and the VH comprises Leu at position 48, Ser at position 76, Val at position 78, Leu at position 79, Phe at position 80, and Thr at position 94.

23. The method of claim 12 , wherein the systemic amyloidosis is AL.

24. The method of claim 12 , wherein the systemic amyloidosis is ATTR.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 23, 2024
From: WALL, JONATHAN S.; FOSTER, JAMES S.
To: UNIVERSITY OF TENNESSEE RESEARCH FOUNDATION
Reel/Frame 068062/0415 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 23, 2024
From: GUTHRIE, SPENCER
To: ATTRALUS, INC.
Reel/Frame 068062/0418 →
Continuity (5)
Division 18181489 · Mar 9, 2023
Continuation 17776827
Provisional Application 63074912 · Sep 4, 2020
Provisional Application 62936002 · Nov 15, 2019
Related Publication 20240294621A1 · Sep 5, 2024
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Martin, E.B. et al. (Nov. 2020). “Looking For Amyloid In All The Right Places,” Journal of Cardiac Failure 26(11):917-918. [cited by applicant]
Martin, E.B. et al. (Sep. 20, 2013). “Characterization Of Peptide 125I-p5R+14 As An Optimized Radiotracer For The In Vivo Detection Of ApoA2c Amyloidosis,” World Molecular Imaging Congress, Savannah, GA, Sep. 18-21, 201… [cited by applicant]
Martin, E.B. et al. (Sep. 7, 2012). “Ex Vivo Identification And In Vivo Validation Of A Novel Visceral Amyloid Imaging Peptide,” World Molecular Imaging Congress, Dublin, Ireland, Sep. 5-8, 2012, Poster Session 3, Prese… [cited by applicant]
Morgan, G.J. et al. (2020). “The Process Of Amyloid Formation Due To Monoclonal Immunoglobulins,” Hematology/Oncology Clinics of North America 34(6):1041-1054. [cited by applicant]
Osborne, D. et al. (Sep. 5, 2012). “I-131 Rodent Imaging On The Inveon SPECT Platform Using A Novel Blended Collimator Acquisition Method,” World Molecular Imaging Congress, Dublin, Ireland, Sep. 5-8, 2012, Poster Sessi… [cited by applicant]
Ramirez-Alvarado, M. et al. (Feb. 12, 2017). “82-Symp. From Native To Amyloid In The Test Tube And In Cells: A Journey Of Misbehaving Antibodies,” Biophys J. 112(3):15a, 1 page. [cited by applicant]
Stuckey, A. et al. (2020). “Dynamic Biodistribution Of 124I-p5+14 In Patients With AL Amyloidosis,” International Symposium on Amyloidosis, Tarragona, Spain, Sep. 14-18, 2020 (virtual), PT046:272, 1 page. [cited by applicant]
Stuckey, A. et al. (May 1, 2017). “Preclinical SPECT/CT Imaging, In A Mouse, Of A Novel Bifunctional Pre-Targeting Peptide For Systemic Amyloidosis Immunotherapy,” Journal of Nuclear Medicine 58 (Suppl 1):1112, 2 pages. [cited by applicant]
Stuckey, A. et al. (May 1, 2018). “Preliminary Pharmacokinetic Study Of A Bispecific Peptide For Pretargeting Immunotherapy Of Amyloidosis Using PreClinical SPECT/CT,” Journal of Nuclear Medicine 59(Suppl 1):1834, 2 pag… [cited by applicant]
Stuckey, A. et al. (May 1, 2019). “Characterization Of A Novel  Sheet-Structured Peptide For Pretargeting Immunotherapy Of Amyloidosis,” Journal of Nuclear Medicine 60(Suppl 1):3021, 2 pages. [cited by applicant]
U.S. Appl. No. 18/907,295, filed Oct. 4, 2024, for Jonathan S. Wall, et al. (U.S. Patent Application is not submitted herewith pursuant to the waiver of 37 C.F.R. § 1.98(a)(2)(iii) issued by the Office on Sep. 21, 2004.… [cited by applicant]
Wall, J. et al. (2022). “Preclinical Characterization Of AT-02, A Pan-Amyloid-Binding Immunoglobulin-Peptide Fusion Protein Capable Of Enhancing Phagocytosis And Facilitating Reduction of Amyloid,” International Society… [cited by applicant]
Wall, J. et al. (2024). “Characterization Of A Novel Beta-Sheet Peptide-Fc Fusion For Targeting Systemic Amyloid Deposits,” International Society of Amyloidosis XIX International Meeting, Rochester, MN, May 2024 254:S10… [cited by applicant]
Wall, J. et al. (2024). “Characterization Of The Peptide-Antibody Fusion, AT-02—Studies To Support Its Use As An Immunotherapy In Patients With Amyloidosis,” Poster, presented at International Society of Amyloidosis XIX… [cited by applicant]
Wall, J. et al. (Jan. 1, 2024). “The Peptide Fusion Immunoglobulin, AT-02, Exhibits Highly Potent Pan-Amyloid Reactivity And Immunomodulation,” Journal of Cardiac Failure 30(1):217, 1 page. [cited by applicant]
Wall, J. et al. (May 1, 2020). “Characterization And In Vivo Target Engagement Studies Of A Novel, Preformed, Amyloid-Reactive Peptope-Antibody Complex,” Journal of Nuclear Medicine 61(Suppl 1) 324:2 pages. [cited by applicant]
Wall, J.S. et al. (2014). “Heparin-Binding Peptides, Basic Fibroblast Growth Factor And p5R, Bind To Different Targets In Amyloid-Laden Mice And Controls,” XIVth International Symposium on Amyloidosis, Indianapolis, IN,… [cited by applicant]
Wall, J.S. et al. (2014). “High Affinity Amyloid-Reactive Peptide, p5R, Binds Non-Uniformly To Large Amyloid Deposits Due To A Binding Site Barrier Effect,” XIVth International Symposium on Amyloidosis, Indianapolis, IN… [cited by applicant]
Wall, J.S. et al. (2014). “Soluble, Recombinant, Receptor For Advanced Glycation End-Products (RAGE) Binds AA Amyloid In Vivo,” XIVth International Symposium on Amyloidosis, Indianapolis, IN, Apr. 28-May 1, 2014, OP-2:2… [cited by applicant]
Wall, J.S. et al. (2014). “Specific Accumulation Of Radiolabeled Peptide p5 In Cerebral Vascular And Parenchymal Aβ Amyloid In Mice,” XIVth International Symposium on Amyloidosis, Indianapolis, IN, Apr. 28-May 1, 2014, … [cited by applicant]
Wall, J.S. et al. (2016). “A Bifunctional Peptide, “Peptope”, For Pre-Targeting Immunotherapy Of Systemic Amyloidosis Evaluated By Using Microautoradiography And SPECT/CT Imaging In A Mouse Model,” 2016 World Molecular … [cited by applicant]
Wall, J.S. et al. (2017, e-pub. Aug. 21, 2017). “Pretargeting Immunotherapy: A Novel Treatment Approach For Systemic Amyloidosis,” Pharmaceutical Patent Analyst 6(5):215-223. [cited by applicant]
Wall, J.S. et al. (2018, e-pub. Oct. 30, 2018). “Bifunctional Amyloid-Reactive Peptide Promotes Binding Of Antibody 11-1F4 To Diverse Amyloid Types And Enhances Therapeutic Efficacy,” PNAS 115(46):E10839-E10848. [cited by applicant]
Wall, J.S. et al. (2020). “Synthesis And Evaluation Of A Novel Peptide-Immunoglobulin Fusion For Targeting And Phagocytosis Of Amyloid,” International Symposium on Amyloidosis, Tarragona, Spain, Sep. 14-18, 2020 (virtua… [cited by applicant]
Wall, J.S. et al. (2023). “Characterization Of AT-02, A Pan-Amyloid-Binding Peptide Fusion Immunoglobulin With High Binding Potency, Complement Activation, And Immune Cell Stimulation,” European Heart Journal 44(Suppl 2… [cited by applicant]
Wall, J.S. et al. (Dec. 26, 2012). “AL Amyloid Imaging And Therapy With A Monoclonal Antibody To A Cryptic Epitope On Amyloid Fibrils,” PloS One 7(12):e52686, 10 pages. [cited by applicant]
Wall, J.S. et al. (May 7, 2012). “Amyloid-Reactive Peptides Bind MelA+ Melanocytes And Extracellular Melanin In Human, Canine And Murine Melanoma Tumors,” XIIIth International Symposium on Amyloidosis, Groningen, Nether… [cited by applicant]
Wall, J.S. et al. (Sep. 18, 2013). “Evaluation Of SPECT Detection Of Cardiac Amyloidosis In Mice By Using 125I-p5R+14 Peptide Or 125I-SAP,” World Molecular Imaging Congress, Savannah, GA, Sep. 18-21, 2013, Poster Sessio… [cited by applicant]
Wall, J.S. et al. (Sep. 19, 2013). “Preliminary Evaluation Of [18F]SFB- And [18F]FBAM-Labeled Amyloidophilic Peptides In Mice With Visceral Amyloidosis,” World Molecular Imaging Congress, Savannah, GA, Sep. 18-21, 2013,… [cited by applicant]
Wall, J.S. et al. (Sep. 7, 2012). “Arginine-Rich Peptide p5R Provides Enhanced Binding To Visceral Amyloid Deposits In Vitro And In Vivo,” World Molecular Imaging Congress, Dublin, Ireland, Sep. 5-8, 2012, Poster Sessio… [cited by applicant]
Wall, J.S. et al. (Sep. 7, 2012). “Heparin-Binding Peptides bFGF And p5R Bind To Different Targets In Amyloid-Laden Mice And Controls,” World Molecular Imaging Congress, Dublin, Ireland, Sep. 5-8, 2012, Poster Session 3… [cited by applicant]
Wall, J.S. et al. (Sep. 8, 2012). “Heparin-Reactive Peptide p5R Preferentially Binds A Subset Of MelA+ Melanocytes And Extracellular Melanin—A Novel Biomarker In Metastatic Melanoma Tumors,” World Molecular Imaging Cong… [cited by applicant]
Wang, Z. et al. (2021). “Computational Investigation Of The Binding Of A Designed Peptide To λ Light Chain Amyloid Fibril,” Physical Chemistry Chemical Physics 23:20634-20644. [cited by applicant]
Wells, K. et al. (May 2012). “Radioimmunoimaging Of Amyloid Deposits In AL Amyloidosis,” Journal of Nuclear Medicine 53(Suppl 1):537, 3 pages. [cited by applicant]