Granted Patent
B2
US 12,441,792 · App. 17/378,050 · Granted Oct 14, 2025
Antibodies specific for immunoglobulin-like transcript 3 (ILT3) and uses thereof
Inventors:
Michael A. Meehl (Northborough, MA); Philip E. Brandish (Needham, MA); Laurence Fayadat-Dilman (Sunnyvale, CA); Veronica Juan (Redwood City, CA); Carl Mieczkowski (Hercules, CA); Latika Singh (Belmont, MA)
Assignee:
Merck Sharp & Dohme LLC
C07K16/2803A61P35/00C07K16/2818A61K2039/505A61K2039/507C07K2317/24C07K2317/32C07K2317/33C07K2317/34C07K2317/76C07K2317/92
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Abstract
Humanized, non-promiscuous monoclonal antibodies specific for immunoglobulin-like transcript 3 (ILT3), also known as Leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4), are described.
Claims (18)
1. A method for treating a subject having a cancer, comprising administering to the subject a therapeutically effective amount of an antibody or antigen binding fragment thereof that binds the extracellular domain of human immunoglobulin-like transcript 3 (ILT3) having amino acids 1-238 of SEQ ID NO: 1, wherein the antibody or antigen binding fragment thereof comprises:
(a) a heavy chain complementarity determining region 1 (HC-CDR1), wherein the HC-CDR1 has the amino acid sequence set forth in SEQ ID NO: 17; an HC-CDR2, wherein the HC-CDR2 has the amino acid sequence set forth in SEQ ID NO: 20; an HC-CDR3, wherein the HC-CDR3 has the amino acid sequence set forth in SEQ ID NO: 23; and
(b) a light chain complementarity determining region 1 (LC-CDR1), wherein the LC-CDR1 has the amino acid sequence set forth in SEQ ID NO: 41; an LC-CDR2, wherein the LC-CDR2 has the amino acid sequence set forth in SEQ ID NO: 43; and an LC-CDR3, wherein the LC-CDR3 has the amino acid sequence set forth in SEQ ID NO: 44,
wherein the cancer is sarcoma, melanoma, lymphoma, leukemia, neuroblastoma, or carcinoma, and wherein the treatment overcomes tumor-specific tolerance.
2. The method of claim 1 , wherein the cancer is melanoma.
3. The method of claim 1 , wherein the V H comprises a framework selected from the group consisting of human V H 1, V H 2, V H 3, V H 4, V H 5, and V H 6, and variants thereof having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof; and, the V L comprises a framework selected from the group consisting of human V κ 1, V κ 2, V κ 3, V κ 4, V κ 5, V κ 6, V λ 1, V λ 2, V λ 3, V λ 4, V λ 5, V λ 6, V λ 7, V λ 8, V λ 9, and V λ 10, and variants thereof having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof.
4. The method of claim 1 , wherein the antibody comprises an HC having a human IgG1, IgG2, IgG3, or IgG4 HC constant domain or variant thereof having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof compared to the amino acid sequence of the native IgG1, IgG2, IgG3, or IgG4 isotype constant domain.
5. The method of claim 4 , wherein the antibody comprises an LC having a human kappa or lambda LC constant domain or variant thereof comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof compared to the amino acid sequence of the native human kappa or lambda light chain constant domain.
6. The method of claim 1 , wherein the antibody comprises:
(i) a V H having a framework selected from the group consisting of human V H 1, V H 2, V H 3, V H 4, V H 5, and V H 6 and a human IgG1 or IgG4 HC constant domain or variant thereof comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof compared to the amino acid sequence of the native IgG1 or IgG4 isotype HC constant domain; and,
(ii) a V L having a framework selected from the group consisting of human V κ 1, V κ 2, V κ 3, V κ 4, V κ 5, V κ 6, V λ 1, V λ 2, V λ 3, V λ 4, V λ 5, V λ 6, V λ 7, V λ 8, V λ 9, and V λ 10 and a human kappa or lambda LC constant domain or variant thereof comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof compared to the amino acid sequence of the native human kappa or lambda LC constant domain.
7. The method of claim 3 , wherein the antibody or antigen binding fragment thereof comprises a V H having the amino acid sequence set forth in SEQ ID NO: 117, 118, 124, or 125 and a V L having the amino acid sequence set forth in SEQ ID NO: 136, or 140.
8. The method of claim 7 , wherein the antibody or antigen binding fragment thereof comprises a V H having the amino acid sequence set forth in SEQ ID NO: 118 and a V L having the amino acid sequence set forth in SEQ ID NO: 140.
9. The method of claim 6 , wherein the antibody comprises a heavy chain (HC) constant domain comprising the amino acid sequence set forth in SEQ ID NO: 9, 10, 11, 12, or 13.
10. The method of claim 6 , wherein the antibody comprises a light chain (LC) constant domain comprising the amino acid sequence set forth in SEQ ID NO: 14.
11. The method of claim 6 , wherein the antibody comprises a heavy chain (HC) comprising the amino acid sequence set forth in SEQ ID NO: 143, 149, 168, 170, 174, 177, 183, 186, or 192.
12. The method of claim 6 , wherein the antibody comprises a light chain (LC) comprising the amino acid sequence set forth in SEQ ID NO: 161, or 165.
13. The method of claim 6 , wherein the antibody comprises a heavy chain (HC) comprising the amino acid sequence set forth in SEQ ID NO: 143 and a light chain (LC) comprising the amino acid sequence set forth in SEQ ID NO: 165, and variants thereof wherein the HC lacks a C-terminal Lysine residue or a C-terminal glycine-lysine.
Assignments (2)
MERGER
Recorded Aug 8, 2022
From: MERCK SHARP & DOHME CORP.
To: MERCK SHARP & DOHME LLC
Reel/Frame 061102/0145 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jul 16, 2021
From: MEEHL, MICHAEL A.; BRANDISH, PHILIP E.; FAYADAT-DILMAN, LAURENCE; JUAN, VERONICA; MIECZKOWSKI, CARL; SINGH, LATIKA
To: MERCK SHARP & DOHME CORP.
Reel/Frame 056883/0278 →
Continuity (3)
Provisional Application
62587604
· Nov 17, 2017
References Cited (194)
US 4439196A
· Higuchi
· 1984
[cited by applicant]
US 4447224A
· DeCant, Jr. et al.
· 1984
[cited by applicant]
US 4487603A
· Harris
· 1984
[cited by applicant]
US 4596556A
· Morrow et al.
· 1986
[cited by applicant]
US 4741900A
· Alvarez
· 1988
[cited by applicant]
US 4790824A
· Morrow et al.
· 1988
[cited by applicant]
US 4816567A
· Cabilly et al.
· 1989
[cited by applicant]
US 4941880A
· Burns
· 1990
[cited by applicant]
US 5064413A
· McKinnon et al.
· 1991
[cited by applicant]
US 5312335A
· McKinnon et al.
· 1994
[cited by applicant]
US 5383851A
· McKinnon, Jr. et al.
· 1995
[cited by applicant]
US 5399163A
· Peterson et al.
· 1995
[cited by applicant]
US 5591828A
· Bosslet et al.
· 1997
[cited by applicant]
US 6096002A
· Landau
· 2000
[cited by applicant]
US 6329511B1
· Vasquez et al.
· 2001
[cited by applicant]
US 6620135B1
· Weston et al.
· 2003
[cited by applicant]
US 7777008B2
· Ponath et al.
· 2010
[cited by applicant]
US 7943743B2
· Korman et al.
· 2011
[cited by applicant]
US 8008449B2
· Korman et al.
· 2011
[cited by applicant]
US 8354509B2
· Carven et al.
· 2013
[cited by applicant]
US 8609089B2
· Langermann
· 2013
[cited by applicant]
US 8691730B2
· Vasquez
· 2014
[cited by applicant]
US 8877688B2
· Vasquez
· 2014
[cited by applicant]
US 8901281B2
· Ponath
· 2014
[cited by applicant]
US 8969526B2
· Baehner
· 2015
[cited by applicant]
US 9296815B2
· D'Angelo
· 2016
[cited by applicant]
US 9708406B2
· Zhang
· 2017
[cited by applicant]
US 20090202544A1
· Suciu-foca
· 2009
[cited by applicant]
US 20100028330A1
· Collins et al.
· 2010
[cited by applicant]
US 20120039906A1
· Olive
· 2012
[cited by applicant]
US 20120114649A1
· Langermann
· 2012
[cited by applicant]
US 20130071403A1
· Rolland et al.
· 2013
[cited by applicant]
US 20150110714A1
· Suciu Foca et al.
· 2015
[cited by applicant]
US 20150139986A1
· Ponath et al.
· 2015
[cited by applicant]
US 20170267759A1
· Liang
· 2017
[cited by applicant]
US 20230084735A1
· Jacob
· 2023
[cited by examiner]
US 20250101097A1
· Wu
· 2025
[cited by examiner]
CN 101830978A
· 2010
[cited by applicant]
EP 404097B1
· 1990
[cited by applicant]
EP 1964852A1
· 2008
[cited by applicant]
EP 042924B1
· 2023
[cited by applicant]
JP 2008543317A
· 2008
[cited by applicant]
JP 2009540828A
· 2009
[cited by applicant]
JP 2017532059A
· 2017
[cited by applicant]
KR 20230158057
· 2023
[cited by examiner]
WO 199311161A1
· 1993
[cited by applicant]
WO 199428027A1
· 1994
[cited by applicant]
WO 2003000199A2
· 2003
[cited by applicant]
WO 2003093474A1
· 2003
[cited by applicant]
WO 2004099249A3
· 2004
[cited by applicant]
WO 2006033811A2
· 2006
[cited by applicant]
WO 2006121168A1
· 2006
[cited by applicant]
WO 2006138739A2
· 2006
[cited by applicant]
WO 2007005874A2
· 2007
[cited by applicant]
WO 2008094176A2
· 2008
[cited by applicant]
WO 2008117049A1
· 2008
[cited by applicant]
WO 2009101611A1
· 2009
[cited by applicant]
WO 2009114335A3
· 2009
[cited by applicant]
WO 2010027827A2
· 2010
[cited by applicant]
WO 2010077634A1
· 2010
[cited by applicant]
WO 2011066342A2
· 2011
[cited by applicant]
WO 2011127543A1
· 2011
[cited by applicant]
WO 2013033734A1
· 2013
[cited by applicant]
WO 2013043569A1
· 2013
[cited by applicant]
WO 2013181438A2
· 2013
[cited by applicant]
WO 2014116846A3
· 2014
[cited by applicant]
WO 2016028672A1
· 2016
[cited by applicant]
WO 2016049641A1
· 2016
[cited by applicant]
WO 2016127427A1
· 2016
[cited by applicant]
WO 2016144728A2
· 2016
[cited by applicant]
WO 2017015227A1
· 2017
[cited by applicant]
WO 2017087589A2
· 2017
[cited by applicant]
WO 2018089300A1
· 2018
[cited by applicant]
WO 2018148494A1
· 2018
[cited by applicant]
Grimmett et al (Discover Oncology (2022) 13:31; published on-line May 16, 2022).
[cited by examiner]
Tian et al (Front Oncol. 2020; 10: 1696; Published online Sep. 11, 2020).
[cited by examiner]
Chuprin, J., Buettner, H., Seedhom, M.O. et al. Humanized mouse models for immuno-oncology research. Nat Rev Clin Oncol 20, 192-206 (2023).
[cited by examiner]
Chen et al (Frontiers in Hematology 1:1062705; pp. 1-12 (Jan. 16, 2023)).
[cited by examiner]
R&D Systems, Human LILRB4/CD85k/ILT3 Antibody, bio-techne, 2018, 1, Clone #293622, Catalog #MAB2425.
[cited by applicant]
U.S. Appl. No. 16/191,485, filed Nov. 15, 2018.
[cited by applicant]
Agata et al., Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes, International Immunology, 1996, pp. 765-772, vol. 8, No. 5.
[cited by applicant]
Armour et al., Recombinant Human IgG Molecules Lacking Fcy receptor I Binding and Monocyte Triggering Activities, Eur. J. Immunol., 1999, pp. 2613-2624, 29.
[cited by applicant]
Baca et al., Antibody Humanization Using Monovalent Phage Display, J. Biol. Chem., 1997, 10678-10684, 272.
[cited by applicant]
Baert et al., Influence of Immunogenicity on the long term efficacy of Infliximab in Crohns disease, New England Journal Med., 2003, pp. 601-608, 348.
[cited by applicant]
Barbas et al., Synthetic Human Antibodies, Nature Medicine, 1995, pp. 837-839, 1.
[cited by applicant]
Beiboer, Sigrid H. W. et al., Guided Selection of a Pan Carcinoma Specific Antibody Reveals Similar Binding Characteristics yet Structural Divergence Between the Original Murine Antibody and its Human Equivalent, J. Mol…
[cited by applicant]
Beniaminovitz et al., Prevention of rejection in cardiac transplantation by blockade of the interleukin 2 receptor with a monoclonal antibody, New England Journal of Medicine, 2000, pp. 613-619, 342.
[cited by applicant]
Bennett et al., Program Death-1 Engagement Upon TCR Activation Has Distinct Effects on Costimulation and Cytokine-Driven Proliferation: Attenuation of ICOS, IL-4, and IL-21, But Not CD28, IL-7, and IL-15 Responses, The …
[cited by applicant]
Blank et al., Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic Infections, Cancer Immunol. Immunother., 2007, pp. 739-745, vol. 56(5).
[cited by applicant]
Blank, Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: Implications for tumor immunotherapy, Cancer Immunol. Immunother., 2005, pp. 307-314, 54.
[cited by applicant]
Brorson, Kurt et al., Mutational Analysis of Avidity and Fine Specificity of Anti-Levan Antibodies, The Journal of Immunology, 1999, 6694-6701, 163.
[cited by applicant]
Brown, Blockade of Programmed Death-1 Ligands on Dendritic Cells Enhances T Cell Activation and Cytokine Production, J. Immunol., 2003, pp. 1257-1266, vol. 170.
[cited by applicant]
Brummell, David A. et al., Probing the Combining Site of an anti-Carbohydrate Antibody by Saturation-Mutagenesis: role of the Heavy-Chain CDR3 Residues, Biochemistry, 1993, 1180-1187, 32.
[cited by applicant]
Burks, Elizabeth A. et al., In vitro scanning saturation mutagenesis of an antibody binding pocket, Proc. Natl. Acad. Sci. USA, 1997, 412-417, 94.
[cited by applicant]
Carpenter et al., Non-Fc Receptor-Binding Humanized Anti-CD3 Antibodies Induce Apoptosis of Activated Human T Cells, J. Immunol., 2000, 6205-6213, 165.
[cited by applicant]
Carter et al., PD-1:PD-L Inhibitory Pathway Affects Both CD4 Plus and CD8 Plus and CD8 Plus T Cells and is overcome by IL-2, Eur. J. Immunol., 2002, pp. 634-643, 32.
[cited by applicant]
Casset, A peptide mimetic of an anti-CD4 monoclonal antibody by rational design, BBRC, 2003, pp. 198-205, 307.
[cited by applicant]
Cella et al., A Novel Inhibitory Receptor (ILT3) Expressed on Monocytes, Macrophages, and Dendritic Cells Involved in Antigen Processing, J. Exp. Med., 1997, Issue 10, pp. 1743-1751, 185.
[cited by applicant]
Cheung et al., Epitope-specific antibody response to the surface antigen of duck hepatitis B virus in infected ducks, Virology, 1990, pp. 546-552, 176.
[cited by applicant]
Chothia and Lesk et al, Canonical Structures for the Hypervariable Regions of Immunoglobins, J. Mol. Biol., 1987, 901-917, 196.
[cited by applicant]
Chothia et al., Conformations of immunoglobin hypervariable regions, Nature, 1989, 877-883, 342.
[cited by applicant]
Clackson et al., Making Antibody Fragments Using Phage Display Libraries, Nature, 1991, pp. 624-628, vol. 352.
[cited by applicant]
Colman, Effects of amino acid sequence changes on antibody-antigen interactions, Research Immunology, 1994, 33-36, 145.
[cited by applicant]
Columbia University in the City of New York, Recombinant ILT3 protein for the treatment of cancer, Columbia Technology Ventures, 2015, 1-2, N/A.
[cited by applicant]
Cunningham et al., High resolution Epitope mapping of hgH-receptor interactions by alanine-scanning mutagenesis, Science, 1985, pp. 1081-1085, 244.
[cited by applicant]
Depascalis, R et al., Grafting of “Abbreviated” Complementarity-Determining Regions Containing Specificity-Determining Residues Essential for Ligand Contact to Engineer a Less Immunogenic Humanized Monoclonal Antibody, …
[cited by applicant]
Dong et al., B7-H1 pathway and its role in the envasion of tumor immunity, J. Mol. Med., 2003, pp. 281-287, 81.
[cited by applicant]
Dufner, Patrick et al., Harnessing phage and ribosome display for antibody optimisation, Trends in Biotechnology, 2006, 523-529, 24(11).
[cited by applicant]
Everts et al., Selective Intracellular Delivery ofDexamethasone into Activated Endothelial Using an E-Selectin-Directed Immunoconjugate, J. Immunol., 2002, pp. 883-889, 168.
[cited by applicant]
Foote et al., Antibody Framework Residues Affecting the Conformation of the Hypervariable Loops, J. Mol. Biol., 1992, pp. 487-499, vol. 224.
[cited by applicant]
Freeman et al., Engagement of the PD-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation, J. Exp. Med., 2000, pp. 1027-1034, vol. 192.
[cited by applicant]
Ghosh et al., Natalizumab for active Crohns disease, New England J. Med., 2003, pp. 24-32, 348.
[cited by applicant]
Gibellini et al., Extracellular HIV-1 Tat Protein Induces the Rapid Ser 133 Phosphorylation and Activation of CREB Transcription Factoer in Both Jurkat Lymphoblastoid T Cells and Primary Blood Mononuclear Cells, J. Immu…
[cited by applicant]
Hamid et al., Safety and Tumor Responses with Lambrolizumab (Anti-PD-1) in Melanoma, New Eng. J. Med., 2013, 134-144, 369(2).
[cited by applicant]
He et al., Humanization and Pharmacokinectics of a Monoclonal Antibody with Specificity for both E-and P-Selectin, J. Immunol., 1998, pp. 1029-1035, 160.
[cited by applicant]
Herold, Anti-CD3 Monoclonal Antibody in New-Onset Type 1 Diabetes Mellitus, New England Journal of Medicine, pp. 1692-1698, 346.
[cited by applicant]
Herren Wu et al., Humanization of a Murine Monoclonal Antibody by Stimultaneous Optimization of Framework and CDR Residues, J. Mol. Biol., 1999, 151-162, 294.
[cited by applicant]
Holliger et al., Diabodies, Proc. Natl. Acad. Sci. USA, 1993, No. 14, pp. 6444-6448, 90.
[cited by applicant]
Holliger et al., Engineered antibody fragments and the rise of single domains, Nat. Biotechnol., 2005, pp. 1126-1136, 23.
[cited by applicant]
Hoogenboom et al., Natural and designer binding sites made by phage display technology, Immunol. Today, 2000, pp. 371-377, 21.
[cited by applicant]
Hsing et al., Requirement for Nuclear Factor-kBActivation by a Distinct Subset of CD40-Mediated Effector Functions in B Lymphocytes, J. Immunol., 1999, pp. 2804-2811, 162.
[cited by applicant]
Inui, et al., Tolerogenic immunoreceptor ILT3/LILRB4 paradoxically marks pathogenic auto-antibody-producing plasmablasts and plasma cells in non-treated SLE, International Immunology, 2016, 597-604, 28(12).
[cited by applicant]
Ishida et al., Induced expression of PD-1, a noval member of the immunoglobulin gene superfamily, upon programmed cell death, The EMBO Journal, 1992, pp. 3887-3895, vol. 11(11).
[cited by applicant]
Iwai, Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade, Proc. Natl. Acad. Sci. USA, 2002, pp. 12293-12297, vol. 99.
[cited by applicant]
Jang, Y.J. et al., The structural basis for DNA binding by an anti-DNA autoantibody, Molecular Immunology, 1998, 1207-1217, 35.
[cited by applicant]
Kabat, the Structural Basis of Antibody Complementarity, Adv. Prot. Chem., 1978, 1-75, 32.
[cited by applicant]
Kabat, Unusual Distributions of Amino Acids in Complementarity-determining (Hypervriable) Segment of Heavy and Light Chains of Immunoglobulins and Their Possible Roles in Specificity of Antibody-combining Sites, J. Biol…
[cited by applicant]
Kang, Xunlei et al., Inhibitory leukocyte immunoglobulin-like receptors: Immune checkpoint proteins and tumor sustaining factors, Cell Cycle, 2015, 25-40, 15(1).
[cited by applicant]
Kirkland et al., Analysis of the fine specificity and cross-reactivity of monoclonal anti-lipid A antibodies, J. Immunol., 1986, pp. 3614-3619, 137.
[cited by applicant]
Klimka, A. et al., Human anti-CD30 recombinant antibodies by guided phage antibody selection using cell panning, British Journal of Cancer, 2000, 252-260, 83(2).
[cited by applicant]
Kobayashi, Hiroyski et al., Tryptophan H33 plays an important role in pyrimidine (6-4) pyrimidone photoproduct binding by a high-affinity antibody, Protein Eng., 1999, 879-884, 12(10).
[cited by applicant]
Kohler et al., Continuous Cultures of Fused Cells Secreting Antibody of Predefined Specificity, Nature, 1975, pp. 195-497, vol. 256.
[cited by applicant]
Kolker, Daniel, Antibodies and the written description requirement of 35 U.S.C.112(a), United States Patent and Trademark Office, 2020, 1-36, N/A.
[cited by applicant]
Konishi et al., B7-H1 Expression on Non-Small Cell Lung Cancer Cells and Its Relationship with Tumor-Infiltrating Lymphocytes and Their PD-1 Expression, Clin. Cancer Res., 2004, pp. 5094-5100, 10.
[cited by applicant]
Kostelny et al., Formation of a bispecific antibody by the use of leucine zippers, J. Immunol., 1992, pp. 1547-1553, 148.
[cited by applicant]
Kumar, Sanjeev et al., Molecular Cloning and Expression of the Fabs of Human Autoantibodies in
[cited by applicant]
Le Doussal et al., Enhanced in vivo targeting of an asymmetric bivalent hapten to double-antigen-positive mouse B cells with monoclonal antibody conjugate cocktails, J. Immunol., 1991, pp. 169-175, 146.
[cited by applicant]
Lipsky et al., Infliximab and methotrexate in the treatment of rheumatoid arthritis, New England Journal of Medicine, 2000, pp. 1594-1602, 343.
[cited by applicant]
Liu et al., Randomised, double blind, placebo controlled study of interferon b-1a in relapsing-remitting multiple sclerosis analysed by area under disability/time curves, N. Neurol. Neurosurg. Psych., 1999, pp. 451-456,…
[cited by applicant]
Maccallum, RM et al., Antibody-antigen interactions: Contact analysis and binding site topography, J. Mol. Biol., 1996, pp. 732-745, 262.
[cited by applicant]
Marks et al., By passing Immunization, J. Mol. Biol., 1991, pp. 581-597, 222.
[cited by applicant]
Meene et al., A comparison of signal sequence prediction methods using a test set of signal peptides, Bioinformatics, 2000, pp. 741-742, 16.
[cited by applicant]
Mendez et al., Functional Transplant of Megabase Human Immunoglobulin loc Recapitulates Human Antibody Response in Mice, Nature Genetics, 1997, pp. 146-156, 15.
[cited by applicant]
Milgrom et al., Treatment of allergic asthma with monoclonal anti IgE antibody, New England Journal Med., 1999, pp. 1966-1973, 341.
[cited by applicant]
Moldenhauer et al., Identity of HML-1 Antigen on Intestinal Intra Epithelial T Cells and of B-1y7 Antigen on Hairy Cell Leukemia, Scan. J. Immunol., 1990, pp. 77-82, 32.
[cited by applicant]
Morel et al., Monoclonal Antibodies to Bovine Serum Albumin: Affinity and Specificity Determinations, Mol. Immunol., 1988, Issue No. 1, pp. 7-15, 25.
[cited by applicant]
Morrison, Sherie L. et al., Chimeric human antibody molecules: Mouse antigen-binding domains with human constant region domains, Proc. Natl. Acad. Sci. USA, 1984, 6851-6855, 81.
[cited by applicant]
Okazaki et al., New regulatory co-receptors: inducible co-stimulator and PD1, Curr. Opin. Immunol., 2002, pp. 779-782, 14.
[cited by applicant]
Patrik Holm et al., Functional mapping and single chain construction of ant-cytokeratin 8 monoclonal antibody TS1, Molecular Immunology, 2007, 1075-1084, 44.
[cited by applicant]
Portielje, IL-12: a promising adjuvant for cancer vaccination, Cancer Immunol Immunother, 2003, 133-144, 52.
[cited by applicant]
Presta, Leonard G. et al., Selection, design, and engineering of therapeutic antibodies, J. Allergy Clin. Immunol., 2005, 731-736, 116(4).
[cited by applicant]
Rader et al., A phage display approach for rapid antibody humanization: Designed combinatorial V gene libraries, Proc. Natl. Acad. Sci. USA, 1998, pp. 8910-8915, 95.
[cited by applicant]
Rudikoff, S. et al., Single amino acid substitution altering antigen-binding specificity, PNAS, 1982, pp. 1979-1983, 79.
[cited by applicant]
Samaridis et al., Cloning of novel immunoglobulin superfamily receptors expressed on human myeloid and lymphoid cells: structural evidence for new stimulatory and inhibitory pathways, Eur. J. Immunol., 1997, Issue 3, pp…
[cited by applicant]
Sela-Culang, Inbal, The structural basis of antibody-antigen recognition, Frontiers in Immunology, 2013, 1-13, 4:302.
[cited by applicant]
Shields, High Resolution Mapping of the Binding Site on Human IgG1 for FcyRI, FcyRII, FcyRIII, and FcRn and Design of IgG1 Variants with Improved Binding to the FeyR, J. of Biol. Chem., 2001, 6591-6604, 276-9.
[cited by applicant]
Slamon et al., Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2, New England J. Med., 2001, pp. 783-792, 344.
[cited by applicant]
Smith-Gill, Sandra J. et al., Contributions of Immunoglobulin Heavy and Light Chains to Antibody Specificity for Lysozyme and Two Haptens, The Journal of Immunology, 1987, 4135-4144, 139.
[cited by applicant]
Sondermann et al., The 3.2-Angstrom Crystal Structure of the Human IgG1 Fc Fragment-Fc gamma RIII Complex, Nature, 2000, pp. 267-273, 406.
[cited by applicant]
Song, Mi-Kyung et al., Light Chain of Natural Antibody Plays a Dominant Role in Protein Antigen Binding, Biochemical and Biophysical Research Communications, 2000, 390-394, 268.
[cited by applicant]
Songsivilai et al., Bispecific antibody: a tool for diagnosis and treatment of disease, Clin. Exp. Immunol., 1990, pp. 315-321, 79.
[cited by applicant]
Stahli et al., Distinction of Epitopes by monoclonal antibodies, Methods in Enzymology, 1983, pp. 242-253, 9.
[cited by applicant]
Tang et al., Use of a Peptide Mimotope to Guide the Humanization of MRK-16, an Anti-P-glycoprotein Monoclonal Antibody, J. Biol. Chem., 1999, pp. 27371-27378, 274.
[cited by applicant]
Traunecker et al., Bispecific single chain molecules (Janusins) target cytotoxic lymphocytes on HIV infected cells, Embo J., 1991, pp. 3655-3659, 10.
[cited by applicant]
Traunecker et al., Janusin: New Molecular Design for Bispecific Reagents, Int. J. Cancer Suppl., 1992, pp. 51-52, 7.
[cited by applicant]
Vajdos, FF et al., Comprehensive functional maps fo the antigen binding site of an anti-ErbB2 antibody obtained with shotgun scanning mutagenesis, Journal of Molecular Biology, 2002, pp. 415-428, 320(2).
[cited by applicant]
Vaughan et al., Human Antibodies with Sub-nanomolar affinities isolated from a large non-immunized phage display library, Nature Biotechnology, 1996, pp. 309-314, vol. 14.
[cited by applicant]
Von Heijne et al., A new method for predkting signal sequence cleavage sites, Nucleic Acids Res., 1986, pp. 1683-4690, 14.
[cited by applicant]
Von Heijne, Patterns of Amino Acids near Signal-Sequence Cleavage Sites, Eur. J. Biochem., 1983, pp. 17-21, 133.
[cited by applicant]
Ward, E. Sally et al., Binding activities of a repertoire of single immunoglobulin variable domains secreted from
[cited by applicant]
Watson et al., The fine structure of bacterial and phage genes, Molecular biology of the gene, 1987, pp. 224-238, 4.
[cited by applicant]
Wren et al., SIGNAL-Sequence Information and GeNomic AnaLysis, Comput. Methods Programs Biomed., 2002, pp. 177-181, 68.
[cited by applicant]
Xu, JL et al., Diversity in the CDR3 region of Vh is sufficient for most antibody specificities, Immunity, 2000, pp. 37-45, 13.
[cited by applicant]
Xu, Zheng et al., ILT3.Fc-CD166 Interaction Induces Inactivation of p70 S6 Kinase and Inhibits Tumor Cell Growth, The Journal of Immunology, 2017, 1207-1219, 200.
[cited by applicant]
Yang et al., A Randomized Trial of Bevacizumab, an Anti-Vascular Endothelial Growth Factor Antibody, for Metastatic Renal Cancer, New England Journal of Medicine, 2003, pp. 427-434, 349.
[cited by applicant]
Yang et al., Identification of the ebola virus glycoprotein as the main viral determinant of vascular cell cytotoxicity and injury, Natl. Med., 2000, pp. 886-889, 6.
[cited by applicant]
Yvonne Chen et al., Selection and Analysis of an Optimized Anti-VEGF Antibody: Crystal Structure of an Affinity-matured Fab in Complex with Antigen, J. Mod. Biol., 1999, 865-881, 293.
[cited by applicant]
Akbar, Rahmad et al., A compact vocabulary of paratope-epitope interactions enables predictability of antibody-antigen binding, Cell Reports, 34, 108856, 1-15, e1-e5, 2021.
[cited by applicant]
Almagro, Juan C. et al., Humanization of antibodies, Frontiers in Bioscience, 13, 1619-1633, 2008.
[cited by applicant]
Altshuler, E. P. et al., Generation of Recombinant Antibodies and Means for Increasing Their Affinity, Biochemistry (Moscow), vol. 75, No. 13, 1584-1605, 2010.
[cited by applicant]
Edwards, B. et al., The Remarkable Flexibility of the Human Antibody Repertoire; Isolation of Over One Thousand Different Antibodies to a Single Protein, BLyS, Jounal of Molecular Biology, 334, 103-118, 2003.
[cited by applicant]
Elek Molnar, Cell-Based Enzyme-Linked Immunosorbent Assay (Cell-ELISA) Analysis of Native and Recombinant Glutamate Receptors, Methods in Molecular Biology, 1941, 47-54, 2019.
[cited by applicant]
George et al., Differential Effects of Anti-Beta2-Glycoprotein I Antibodies on Endothelial Cells and on the Manifestations of Experimental Antiphospholipid Syndrome, Circulation, vol. 97, pp. 900-906, 1998.
[cited by applicant]
Gundle, Kenneth et al., Evaluation of the Effects of Pembrouzumab Alone and in Combination(S) With MDSC-Targeting Agents MK-0482 and MK-4830 on the Native Cancer Patient TME VIA Functional Spatial Profiling (CIVO, J Imm…
[cited by applicant]
Hasegawa, Haruki et al., Single amino acid substitution in LC-CDR1 induces Russell body phenotype that attenuates cellular protein synthesis through elF2α phosphorylation and thereby downregulates IgG secretion despite …
[cited by applicant]
Lippow, Shaun M et al., Computational design of antibody-affinity improvement beyond in vivo maturation, Nature Biotechnology, 25(10), 1171-1176, 2007.
[cited by applicant]
Lo, Ying-Tsang et al., Conformational epitope matching and prediction based on protein surface spiral features, BMC Genomics, 22(Suppl 2):116, 1-16, 2021.
[cited by applicant]
Marchalonis, J.J. et al., The antibody repertoire in evolution: Chance, selection, and continuity, Developmental and Comparative Immunology, 30, 223-247, 2006.
[cited by applicant]
Marks, Claire et al., How repertoire data are changing antibody science, J. Biol. Chem., 295(29), 9823-9837, 2020.
[cited by applicant]
Sela-Culang, Lnbal et al., Using a Combined Computational-Experimental Approach to Predict Antibody-Specific B Cell Epitopes, Structure, 22, 646-657, 2014.
[cited by applicant]
Sulea, Traian et al., Application of Assisted Design of Antibody and Protein Therapeutics (ADAPT) improves efficacy of a Clostridium difficile toxin A singledomain antibody, Scientific Reports, 8:2260, 1-11, 2018.
[cited by applicant]
Vajda, Sandor et al., Progress toward improved understanding of antibody maturation, Current Opinion in Structural Biology, 67, 226-231, 2021.
[cited by applicant]