IP Library › Granted Patent US 12,269,877
Granted Patent B2
US 12,269,877 · App. 16/992,897 · Granted Apr 8, 2025

Anti-notch3 antibodies

Inventors: Heidi Okamura (Brookline, MA); Sandra Abbott (Boston, MA); Alisa C. Bell (Bedford, MA); Kelly Kreuter (Arvada, CO); Ronan O'Hagan (Arlington, MA); Samantha Perino (Brighton, MA); Hamid Tissire (Abington, MA); William M. Winston, Jr. (Marlborough, MA); Jeno Gyuris (Lincoln, MA)
Assignee: AVEO Pharmaceuticals, Inc.
C07K16/28A61K39/3955C12N15/09C12N15/63A61K2039/505C07K16/2863C07K2317/14C07K2317/24C07K2317/515C07K2317/56C07K2317/565C07K2317/76C07K2317/92C12N5/10C12N5/12C12N5/16
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Quick Facts
Patent No.
US 12,269,877
App. No.
16/992,897
Granted
Apr 8, 2025
Kind
B2
Abstract

Monoclonal antibodies that bind and inhibit activation of human Notch3 are disclosed. The antibodies can be used to treat cell proliferative diseases and disorders, including certain forms of cancer, associated with activation of Notch3.

Claims (37)

1. A method of inhibiting or reducing ligand-induced Notch3 activity, comprising administering 0.5-20 mg/kg of an anti-Notch3 antibody, or antigen-binding fragment thereof, to a mammal, wherein the anti-Notch3 antibody comprises an immunoglobulin heavy chain variable region (VH) and an immunoglobulin light chain variable region (VL) selected from the group consisting of:

(a) (i) a VH comprising a CDR H1 comprising the amino acid sequence of SEQ ID NO:51, a CDR H2 comprising the amino acid sequence of SEQ ID NO:53, and a CDR H3 comprising the amino acid sequence of SEQ ID NO:7; and

(ii) a VL comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO:62, a CDR L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR L3 comprising the amino acid sequence of SEQ ID NO: 10; and

(b) (i) a VH comprising a CDR H1 comprising the amino acid sequence of SEQ ID NO:51, a CDR H2 comprising the amino acid sequence of SEQ ID NO:53, and a CDR H3 comprising the amino acid sequence of SEQ ID NO:7; and

(ii) a VL comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO:64, a CDR L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR L3 comprising the amino acid sequence of SEQ ID NO: 10.

2. The method of claim 1 , wherein the ligand-induced Notch3 activity is ligand-induced Notch3 intracellular domain (ICD) cleavage.

3. The method of claim 1 , wherein the ligand-induced Notch3 activity is ligand-induced Notch3 receptor signaling and/or ligand-induced Notch3-mediated transcription.

4. The method of claim 1 , wherein the ligand is selected from the group consisting of Jag1, Jag2, DLL1, and DLL2.

5. The method of claim 1 , wherein the mammal is a human.

6. The method of claim 5 , wherein the human is a human cancer patient.

7. The method of claim 1 , wherein the VH and the VL are selected from the group consisting of:

(a) a VH comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO:36, and a VL comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO:46;

(b) a VH comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ TD NO:38, and a VL comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ TD NO:46; and

(c) a VH comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO:36, and a VL comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO:50.

8. The method of claim 1 , wherein the VH and the VL are selected from the group consisting of:

(a) a VH comprising the amino acid sequence of SEQ TD NO:36, and a VL comprising the amino acid sequence of SEQ TD NO:46;

(b) a VH comprising the amino acid sequence of SEQ ID NO:38, and a VL comprising the amino acid sequence of SEQ ID NO:46; and

(c) a VH comprising the amino acid sequence of SEQ ID NO:36, and a VL comprising the amino acid sequence of SEQ ID NO:50.

9. The method of claim 1 , wherein the anti-Notch3 antibody comprises an immunoglobulin heavy chain (HC) and an immunoglobulin light chain (LC) selected from the group consisting of:

(a) an HC comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ TD NO: 78, and an LC comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 90;

(b) an HC comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 80, and an LC comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 90; and

(c) an HC comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 78, and an LC comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 94.

10. The method of claim 1 , wherein the anti-Notch3 antibody comprises an immunoglobulin heavy chain (HC) and an immunoglobulin light chain (LC) selected from the group consisting of:

(a) an HC comprising the amino acid sequence of SEQ ID NO: 78, and an LC comprising the amino acid sequence of SEQ ID NO: 90;

(b) an HC comprising the amino acid sequence of SEQ ID NO: 80, and an LC comprising the amino acid sequence of SEQ ID NO: 90; and

(c) an HC comprising the amino acid sequence of SEQ ID NO: 78, and an LC comprising the amino acid sequence of SEQ ID NO: 94.

11. The method of claim 1 , wherein the method comprises administering 20 mg/kg of the anti-Notch3 antibody.

12. A method of inhibiting or reducing ligand-induced Notch3 activity, comprising administering 0.5-20 mg/kg of an anti-Notch3 antibody, or antigen-binding fragment thereof, to a mammal, wherein the anti-Notch3 antibody comprises the HC-CDR1, HC-CDR2, and HC-CDR3 amino acid sequences of a VH and comprises the LC-CDR1, LC-CDR2 and LC-CDR3 amino acid sequences of a VL wherein:

(a) the VH comprises the amino acid sequence of SEQ ID NO:36, and the VL comprises the amino acid sequence of SEQ ID NO:46;

(b) the VH comprises the amino acid sequence of SEQ ID NO:38, and the VL comprises the amino acid sequence of SEQ ID NO:46; and

(c) the VH comprises the amino acid sequence of SEQ ID NO:36, and the VL comprises the amino acid sequence of SEQ ID NO:50.

13. The method of claim 12 , wherein the ligand-induced Notch3 activity is ligand-induced Notch3 intracellular domain (ICD) cleavage.

14. The method of claim 12 , wherein the ligand-induced Notch3 activity is ligand-induced Notch3 receptor signaling and/or ligand-induced Notch3-mediated transcription.

15. The method of claim 12 , wherein the ligand is selected from the group consisting of Jag1, Jag2, DLL1, and DLL2.

16. The method of claim 12 , wherein the mammal is a human.

17. The method of claim 16 , wherein the human is a human cancer patient.

18. The method of claim 12 , wherein the method comprises administering 20 mg/kg of the anti-Notch3 antibody.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 3, 2020
From: OKAMURA, HEIDI; ABBOTT, SANDRA; BELL, ALISA C.; KREUTER, KELLY; O'HAGAN, RONAN; PERINO, SAMANTHA; TISSIRE, HAMID; WINSTON, WILLIAM M., JR.; GYURIS, JENO
To: AVEO PHARMACEUTICALS, INC.
Reel/Frame 054527/0187 →
Continuity (5)
Continuation 15864710 · Jan 8, 2018
Continuation 14653684
Provisional Application 61866787 · Aug 16, 2013
Provisional Application 61739435 · Dec 19, 2012
Related Publication 20210171627A1 · Jun 10, 2021
References Cited (36)
US 6399857B1 · Kloti · 2002 [cited by applicant]
US 7544476B1 · O'Hagan et al. · 2009 [cited by applicant]
US 8425903B2 · Gurney · 2013 [cited by examiner]
US 9879083B2 · Okamura · 2018 [cited by examiner]
US 10745476B2 · Okamura · 2020 [cited by examiner]
US 20080131908A1 · Li · 2008 [cited by examiner]
US 20080226621A1 · Fung · 2008 [cited by examiner]
US 20100111958A1 · Gurney · 2010 [cited by examiner]
US 20140127211A1 · Geles · 2014 [cited by examiner]
WO WO2008076960A2 · 2008 [cited by examiner]
WO WO2008091641A2 · 2008 [cited by applicant]
WO WO2010005566A2 · 2010 [cited by applicant]
WO WO2011041336A2 · 2011 [cited by applicant]
WO WO2012003472A1 · 2012 [cited by applicant]
WO WO2014100435A1 · 2014 [cited by applicant]
Bellavia et al. Constitutive activation of NF-kappaB and T-cell leukemia/lymphoma in Notch3 transgenic mice. EMBO J 19(13): 3337-3348, 2000. [cited by examiner]
Bellavia et al. Combined expression of pTalpha and Notch3 in T cell leukemia identifies the requirement of preTCR for leukemogenesis. Proc Natl Acad Sci USA 99(6): 3788-3793, 2002. [cited by examiner]
Bellavia et al. Notch3: from subtle structural differences to functional diversity. Oncogene 27: 5092-5098, 2008. [cited by examiner]
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: 103-118, 2003. [cited by examiner]
Haruki et al. Dominant-negative Notch3 receptor inhibits mitogen-activated protein kinase pathway and the growth of human lung cancers. Cancer Res 65(9): 3555-3561, 2005. [cited by examiner]
Joutel et al. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet 358: 2049-2051, 2001. [cited by examiner]
Lloyd et al. Modelling the human immune response: performance of a 10 human antibody repertoire against a broad panel of therapeutically relevant antigens. Prot Eng Design Select 22(3): 159-168, 2009. [cited by examiner]
Park et al. Notch3 gene amplification in ovarian cancer. Cancer Res 66(12): 6312-6318, 2006. [cited by examiner]
Sansone et al. IL-6 riggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest 117(2): 2988-4002, 2007. [cited by examiner]
Aste-Amézaga M et al., “Characterization of Notch1 Antibodies that Inhibit Signaling of Both Normal and Mutated Notch1 Receptors”, PLoS One, 2010, 5(2):e9094. [cited by applicant]
Bray SJ, “Notch Signalling: A Simple Pathway Becomes Complex”, Nat Rev Mol Cell Biol, 2006, 7(9):678-89. [cited by applicant]
International Search Report for Application No. PCT/US2013/076615 (Form ISA/210) dated Aug. 5, 2014 (8 pages). [cited by applicant]
Jaye et al. Isolation of a human anti-haemophilic factor IX cDNA clone using a 52-base synthetic oligonucleotide probe deduced from the amino acid sequence of bovine factor IX. Nucleic Acids Res 11(8): 2325-2335, 1983. [cited by applicant]
Kopan R and Ilagan MX, “The Canonical Notch Signaling Pathway: Unfolding the Activation Mechanism”, Cell, 2009, 137(2):216-33. [cited by applicant]
Lewin, B. Genes IV, Oxford: Oxford University Press, 1990; pp. 118-120. [cited by applicant]
Li K et al., “Modulation of Notch Signaling by Antibodies Specific for the Extracellular Negative Regulatory Region of NOTCH3”, J Biol Chem, 2008, 283(12):8046-54. [cited by applicant]
Lin L et al., “Targeting Specific Regions of the Notch3 Ligand-Binding Domain Influences Apoptosis and Inhibits Tumor Growth in Lung Cancer”, Cancer Res, 2010, 70(2):632-8. [cited by applicant]
Miele Let al., “NOTCH Signaling as a Novel Cancer Therapeutic Target”, Curr Cancer Drug Targets, 2006, 6(4):313-23. [cited by applicant]
Sambrook et al. Molecular Cloning a Laboratory Manual, 2nd edition, Cold Spring Harbor, N.Y., 1989, pp. 2.43-2.84. [cited by applicant]
Written Opinion of the International Searching Authority for Application No. PCT/US2013/076615 (Form ISA/237) dated Aug. 5, 2014 (8 pages). [cited by applicant]
Wu Y et al., “Therapeutic Antibody Targeting of Individual Notch Receptors”, Nature, 2010, 464(7291):1052-7. [cited by applicant]