Patent application EP19170438A (EP), filed 2019-04-19
Publication number: EP3725370A1
Title: MODIFIED ANTI-PD-L1 ANTIBODIES AND METHODS AND USES FOR TREATING A NEURODEGENERATIVE DISEASE
Abstract: [0001]    The present specification discloses anti-PD-L1 antibodies that abolishes Fc-related effector function and enhances clearance rate while maintaining therapeutic efficacy for neurodegenerative disease modification. In addition, the present specification discloses methods of treatment and uses that employ an administration regime of the disclosed anti-PD-L1 antibodies that ensures the antibodies are present for only a specific period of time and then are sufficiently cleared from the body to ensure treatment efficacy is maintained.
IPC codes: A61P  25/    28            A I
C07K  16/    28            A I
Claims: number: 1
text: A modified anti-Programmed Death Ligand 1 (PD-L1) antibody, comprising
a heavy chain comprising a heavy chain variable region including a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a CDR3 of SEQ ID NO: 7 or SEQ ID NO: 8, and a heavy chain constant region of SEQ ID NO: 55; SEQ ID NO: 56 or SEQ ID NO: 57 and
a light chain comprising a light chain variable region including CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13 and a CDR3 of SEQ ID NO: 14 or SEQ ID NO 15.
wherein the modified anti-PD-L1 antibody has a clearance rate from the blood that is enhanced relative to an anti-PD-L1 antibody having a heavy chain constant region of SEQ ID NO: 54 or SEQ ID NO: 108; and
wherein the modified anti-PD-L1 antibody lacks Fc-related effector function.
number: 2
text: The anti-PD-L1 antibody of claim 2, wherein the heavy chain variable region is SEQ ID NO: 2.
number: 3
text: The anti-PD-L1 antibody of claim 3, wherein the heavy chain is SEQ ID NO: 42, SEQ ID NO: 43 or SEQ ID NO: 44.
number: 4
text: The anti-PD-L1 antibody according to any one of claims 1-3, wherein the light chain further comprises a kappa light chain constant region.
number: 5
text: The anti-PD-L1 antibody according to claim 4, wherein the kappa light chain constant region is SEQ ID NO: 16.
number: 6
text: The anti-PD-L1 antibody according to any one of claims 1-5, wherein the light chain is SEQ ID NO: 21.
number: 7
text: A modified anti-Programmed Death Ligand 1 (PD-L1) antibody comprising
a heavy chain comprising a heavy chain variable region of SEQ ID NO: 2 and a heavy chain constant region of SEQ ID NO: 55, SEQ ID NO: 56, or SEQ ID NO: 57; and
a light chain comprising a light chain variable region of SEQ ID NO 9 and a light chain constant region of SEQ ID NO: 16,
wherein the modified anti-PD-L1 antibody has a clearance rate from the blood that is enhanced relative to an unmodified anti-PD-L1 antibody; and
wherein the modified anti-PD-L1 antibody lacks Fc-related effector function.
number: 8
text: A pharmaceutical composition comprising a modified anti-PD-L1 antibody as defined in any one of claims 1-7.
number: 9
text: A pharmaceutical kit comprising a modified anti-PD-L1 antibody as defined in any one of claims 1-7 or a pharmaceutical composition as defined in claim 8.
number: 10
text: A modified anti-PD-L1 antibody as defined in any one of claims 1-7 or a pharmaceutical composition as defined in claim 8 for use in treating an Alzheimer's Disease.
number: 11
text: A polynucleotide comprising a nucleic acid sequence encoding a heavy chain from a modified anti-PD-L1 antibody as defined in any one of claims 1-7 or a nucleic acid sequence encoding a light chain from a modified anti-PD-L1 antibody as defined in any one of claims 1-7.
number: 12
text: The polynucleotide according to claim 11, wherein the nucleic acid sequence encoding the heavy chain comprises SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, or SEQ ID NO: 65 and the nucleic acid sequence encoding the light chain comprises SEQ ID NO: 82 or SEQ ID NO: 83.
number: 13
text: An expression construct comprising a nucleic acid sequence encoding a heavy chain from a modified anti-PD-L1 antibody as defined in claim 11 or 12.
number: 14
text: An expression construct comprising a nucleic acid sequence encoding a light chain from a modified anti-PD-L1 antibody as defined in claim 11 or 12.
number: 15
text: A method of making a modified anti-PD-L1 antibody comprising
expressing in a host cell a first and a second expression construct, wherein the first expression construct is defined by claim 13, and the second expression construct is defined by claim 14.
Office action: search_report, dated 2020-10-21
Rejection reasons: inventive_step_epc_56
Prior art cited: ref_id: US4816567A
ref_type: patent
severity: background
ref_id: US5807715A
ref_type: patent
severity: background
ref_id: US9617338B1
ref_type: patent
severity: background
ref_id: - HOLLIGER, P.; HUDSON, P.J.: "Engineered antibody fragments and the rise of single domains", NAT. BIOTECHNOL., vol. 23, 2005, pages 1126 - 1136, XP008076746, DOI: doi:10.1038/nbt1142
ref_type: npl
severity: background
ref_id: - CUESTA, A.M.; SAINZ-PASTOR, N.; BONET, J.; OLIVA, B.; ALVAREZ-VALLINA, L.: "Multivalent antibodies: when design surpasses evolution", TRENDS BIOTECHNOL., vol. 28, 2010, pages 355 - 362, XP009139358, DOI: doi:10.1016/j.tibtech.2010.03.007
ref_type: npl
severity: background
ref_id: - NELSON, A.L.: "Antibody fragments: hope and hype", MABS, vol. 2, 2010, pages 77 - 83
ref_type: npl
severity: background
ref_id: - PLUCKTHUN: "The Pharmacology of Monoclonal Antibodies", vol. 113, 1994, SPRINGER-VERLAG, pages: 269 - 315
ref_type: npl
severity: background
ref_id: - BORRABECK: "Antibody Engineering", 1995, OXFORD UNIVERSITY PRESS
ref_type: npl
severity: background
ref_id: - CYRUS CHOTHIA ET AL.: "Conformations of Immunoglobulin Hypervariable Regions", NATURE, vol. 342, no. 6252, 1989, pages 877 - 883, XP002030586, DOI: doi:10.1038/342877a0
ref_type: npl
severity: background
ref_id: - ELVIN A. KABAT ET AL.: "Sequences of Proteins of Immunological Interest", 1991, PUBLIC HEALTH SERVICE, NATIONAL INSTITUTES OF HEALTH
ref_type: npl
severity: background
ref_id: - KOHLER ET AL., NATURE, vol. 256, 1975, pages 495
ref_type: npl
severity: background
ref_id: - CLACKSON ET AL., NATURE, vol. 352, 1991, pages 624 - 628
ref_type: npl
severity: background
ref_id: - MARKS ET AL., J. MOL. BIOL., vol. 222, 1991, pages 581 - 597
ref_type: npl
severity: background
ref_id: - JULIE D. THOMPSON ET AL.: "CLUSTAL W: Improving the Sensitivity of Progressive Multiple Sequence Alignment Through Sequence Weighting, Position-Specific Gap Penalties and Weight Matrix Choice", NUCLEIC ACIDS RESEARCH, vol. 22, no. 22, 1994, pages 4673 - 4680, XP002956304
ref_type: npl
severity: background
ref_id: - OSAMU GOTOH: "Significant Improvement in Accuracy of Multiple Protein Sequence Alignments by Iterative Refinement as Assessed by Reference to Structural Alignments", J. MOL. BIOL., vol. 264, no. 4, 1996, pages 823 - 838
ref_type: npl
severity: background
ref_id: - ERIC DEPIEREUX; ERNEST FEYTMANS: "Match-Box: A Fundamentally New Algorithm for the Simultaneous Alignment of Several Protein Sequences", CABIOS, vol. 8, no. 5, 1992, pages 501 - 509
ref_type: npl
severity: background
ref_id: - C. E. LAWRENCE ET AL.: "Detecting Subtle Sequence Signals: A Gibbs Sampling Strategy for Multiple Alignment", SCIENCE, vol. 262, no. 5131, 1993, pages 208 - 214, XP001152872, DOI: doi:10.1126/science.8211139
ref_type: npl
severity: background
ref_id: - IVO VAN WALLE ET AL.: "Align-M - A New Algorithm for Multiple Alignment of Highly Divergent Sequences", BIOINFORMATICS, vol. 20, no. 9, 2004, pages 1428 - 1435
ref_type: npl
severity: background
ref_id: - BURKHARD MORGENSTERN ET AL.: "Multiple DNA and Protein Sequence Alignment Based On Segment-To-Segment Comparison", PROC. NATL. ACAD. SCI. U.S.A., vol. 93, no. 22, 1996, pages 12098 - 12103, XP002908667, DOI: doi:10.1073/pnas.93.22.12098
ref_type: npl
severity: background
ref_id: - CEDRIC NOTREDAME ET AL.: "T-Coffee: A Novel Algorithm for Multiple Sequence Alignment", J. MOL. BIOL., vol. 302, no. 1, 2000, pages 205 - 217, XP004469125, DOI: doi:10.1006/jmbi.2000.4042
ref_type: npl
severity: background
ref_id: - ROBERT C. EDGAR: "MUSCLE: Multiple Sequence Alignment With High Score Accuracy and High Throughput", NUCLEIC ACIDS RES., vol. 32, no. 5, 2004, pages 1792 - 1797, XP008137003, DOI: doi:10.1093/nar/gkh340
ref_type: npl
severity: background
ref_id: - AMARENDRAN R SUBRAMANIAN ET AL.: "DIALIGN-T: An Improved Algorithm for Segment-Based Multiple Sequence Alignment", BMC BIOINFORMATICS, vol. 6, no. 1, 2005, pages 66, XP021000959, DOI: doi:10.1186/1471-2105-6-66
ref_type: npl
severity: background
ref_id: - "PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS", 1999, LIPPINCOTT WILLIAMS & WILKINS PUBLISHERS
ref_type: npl
severity: background
ref_id: - "REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY", 2000, LIPPINCOTT, WILLIAMS & WILKINS
ref_type: npl
severity: background
ref_id: - "GOODMAN & GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS", 2001, MCGRAW-HILL PROFESSIONAL
ref_type: npl
severity: background
ref_id: - RAYMOND C. ROWE ET AL.: "HANDBOOK OF PHARMACEUTICAL EXCIPIENTS", 2003, APHA PUBLICATIONS
ref_type: npl
severity: background
ref_id: - "Handbook of Biodegradable Polymers", 1997, OVERSEAS PUBLISHERS ASSOCIATION
ref_type: npl
severity: background
ref_id: WO2010077634A1
ref_type: patent
severity: background
ref_id: US9617338B1
ref_type: patent
severity: background
ref_id: US2017355770A1
ref_type: patent
severity: background
ref_id: - NETA ROSENZWEIG ET AL: "PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model", NATURE COMMUNICATIONS, vol. 10, no. 1, 28 January 2019 (2019-01-28), XP055630875, DOI: 10.1038/s41467-019-08352-5
ref_type: npl
severity: background
ref_id: - RONG DENG ET AL: "Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor", MABS, vol. 8, no. 3, 26 February 2016 (2016-02-26), US, pages 593 - 603, XP055504015, ISSN: 1942-0862, DOI: 10.1080/19420862.2015.1136043
ref_type: npl
severity: background
ref_id: - JIANMIN LIN ET AL: "The antitumor activity of the human FOLR1-specific monoclonal antibody, farletuzumab, in an ovarian cancer mouse model is mediated by antibody-dependent cellular cytotoxicity", CANCER BIOLOGY & THERAPY, vol. 14, no. 11, 1 November 2013 (2013-11-01), US, pages 1032 - 1038, XP055271961, ISSN: 1538-4047, DOI: 10.4161/cbt.26106
ref_type: npl
severity: background
ref_id: - KIM J-K ET AL: "Mapping the site on human IgG for binding of the MHC class I-related receptor, FcRn", EUROPEAN JOURNAL OF IMMUNOLOGY, WILEY VCH, WEINHEIM, vol. 29, no. 9, 1 September 1999 (1999-09-01), pages 2819 - 2825, XP002300286, ISSN: 0014-2980, DOI: 10.1002/(SICI)1521-4141(199909)29:09<2819::AID-IMMU2819>3.0.CO;2-6
ref_type: npl
severity: background
ref_id: - XINHUA WANG ET AL: "IgG Fc engineering to modulate antibody effector functions", PROTEIN & CELL, vol. 9, no. 1, 6 October 2017 (2017-10-06), Beijing, CN, pages 63 - 73, XP055457296, ISSN: 1674-800X, DOI: 10.1007/s13238-017-0473-8
ref_type: npl
severity: background
ref_id: WO2010077634
ref_type: patent
severity: obviousness
ref_id: US9617338
ref_type: patent
severity: obviousness
ref_id: US2017355770
ref_type: patent
severity: obviousness
ref_id: - NETA ROSENZWEIG ET AL, "PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model", NATURE COMMUNICATIONS, (20190128), vol. 10, no. 1, doi:10.1038/s41467-019-08352-5, XP055630875 [Y] 1-15 * page  2  - page  6, column  r, paragraph  final * * figures 1-3 *
ref_type: npl
severity: obviousness
ref_id: - RONG DENG ET AL, "Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor", MABS, US, (20160226), vol. 8, no. 3, doi:10.1080/19420862.2015.1136043, ISSN 1942-0862, pages 593 - 603, XP055504015 [Y] 1-15 * page  597, paragraph  3  - column  r *
ref_type: npl
severity: obviousness
ref_id: - JIANMIN LIN ET AL, "The antitumor activity of the human FOLR1-specific monoclonal antibody, farletuzumab, in an ovarian cancer mouse model is mediated by antibody-dependent cellular cytotoxicity", CANCER BIOLOGY & THERAPY, US, (20131101), vol. 14, no. 11, doi:10.4161/cbt.26106, ISSN 1538-4047, pages 1032 - 1038, XP055271961 [Y] 1-15 * page  1035, paragraph  bridging  - page  1036 *
ref_type: npl
severity: obviousness
ref_id: - KIM J-K ET AL, "Mapping the site on human IgG for binding of the MHC class I-related receptor, FcRn", EUROPEAN JOURNAL OF IMMUNOLOGY, WILEY VCH, WEINHEIM, (19990901), vol. 29, no. 9, doi:10.1002/(SICI)1521-4141(199909)29:09<2819::AID-IMMU2819>3.0.CO;2-6, ISSN 0014-2980, pages 2819 - 2825, XP002300286 [Y] 1-15 * page  2821, paragraph  1  - column  r * * table 2 *
ref_type: npl
severity: obviousness
ref_id: - XINHUA WANG ET AL, "IgG Fc engineering to modulate antibody effector functions", PROTEIN & CELL, Beijing, CN, (20171006), vol. 9, no. 1, doi:10.1007/s13238-017-0473-8, ISSN 1674-800X, pages 63 - 73, XP055457296 [Y] 1-15 * figure 1; table 1 * * page  69 *
ref_type: npl
severity: obviousness
Final disposition: pending (2020-10-21)