IP Library › Granted Patent US 12,595,304
Granted Patent B2
US 12,595,304 · App. 17/767,894 · Granted Apr 7, 2026

Antibodies specific to glycosylated LAG3 and methods of use thereof

Inventor: Stephen S. Yoo (Centerville, VA)
Assignee: STCube & Co., Inc.
C07K16/2803A61P35/00C07K2317/24C07K2317/41C07K2317/622
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Quick Facts
Patent No.
US 12,595,304
App. No.
17/767,894
Granted
Apr 7, 2026
Kind
B2
Abstract

Antibodies that selectively bind to glycosylated LAG3 relative to unglycosylated LAG3 are provided. In some aspects, LAG3 polypeptides comprising glycosylated amino acid positions are also provided. Methods for making and using such antibodies and polypeptides (e.g., for the treatment of cancer) are also provided.

Claims (21)

1 . An isolated monoclonal antibody which selectively binds to glycosylated LAG3 relative to unglycosylated form of LAG3,

said isolated monoclonal antibody having (I) a V H domain comprising (a) a Chothia CDR H1 with the amino acid sequence of SEQ ID NO: 6, a CDR H2 with the amino acid sequence of SEQ ID NO: 7, and a CDR H3 with the amino acid sequence of SEQ ID NO: 8 (b) an AbM CDR H1 with the amino acid sequence of SEQ ID NO: 9, a CDR H2 with the amino acid sequence of SEQ ID NO: 10, and a CDR H3 with the amino acid sequence of SEQ ID NO: 8; or (c) a Kabat CDR H1 with the amino acid sequence of SEQ ID NO: 11, a CDR H2 with the amino acid sequence of SEQ ID NO: 12, and a CDR H3 with the amino acid sequence of SEQ ID NO: 8; and (II) a VL domain comprising a CDR L1 with the amino acid sequence of SEQ ID NO: 16, a CDR L2 with the amino acid sequence of SEQ ID NO: 17, and a CDR L3 with the amino acid sequence of SEQ ID NO: 18, or

said isolated monoclonal antibody having (I) a V H domain comprising a Contact CDR H1 with the amino acid sequence of SEQ ID NO: 13, a CDR H2 with the amino acid sequence of SEQ ID NO: 14, and a CDR H3 with the amino acid sequence of SEQ ID NO: 15 and (II) a VL domain comprising a Contact CDR L1 with the amino acid sequence of SEQ ID NO: 19, a CDR L2 with the amino acid sequence of SEQ ID NO: 20, and a CDR L3 with the amino acid sequence of SEQ ID NO: 21.

2 . The isolated antibody of claim 1 , wherein the antibody increases secretion of IFN-γ and/or IL-2 or wherein the antibody increases T-cell proliferation.

3 . The isolated antibody of claim 1 , wherein the antibody selectively binds to LAG3 glycosylated at positions N188, N250, N256, N343, or any combination thereof, relative to unglycosylated LAG3 and wherein the antibody blocks binding of LAG3 to one or more of Gal-3, MHCII, LSECtin, and CD3 and wherein the binding affinity of anti-glycLAG3 antibodies for glycosylated LAG3 is from 0.1-10 nM inclusive of the lower and upper values.

4 . The isolated antibody of claim 1 , wherein the V H domain has an amino acid sequence of SEQ ID NO: 3 and the V L has an amino acid sequence of SEQ ID NO: 5.

5 . The isolated antibody of claim 1 , wherein the V H domain has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 3.

6 . The isolated antibody of claim 1 , wherein the V L domain has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 5.

7 . The isolated antibody of claim 1 , which has a V H domain comprising a Chothia CDR H1 with an amino acid sequence of SEQ ID NO: 6, a CDR H2 with an amino acid sequence of SEQ ID NO: 7, and a CDR H3 with an amino acid sequence of SEQ ID NO: 8 or which has a V H domain comprising a AbM CDR H1 with an amino acid sequence of SEQ ID NO: 9, a CDR H2 with an amino acid sequence of SEQ ID NO: 10, and a CDR H3 with an amino acid sequence of SEQ ID NO: 8 or which has a V H domain comprising a Kabat CDR H1 with an amino acid sequence of SEQ ID NO: 11, a CDR H2 with an amino acid sequence of SEQ ID NO: 12, and a CDR H3 with an amino acid sequence of SEQ ID NO: 8 and which has a V L domain comprising a CDR L1 with an amino acid sequence of SEQ ID NO: 16, a CDR L2 with an amino acid sequence of SEQ ID NO: 17, and a CDR L3 with an amino acid sequence of SEQ ID NO: 18.

8 . The isolated antibody of claim 1 , which has a V H domain comprising a Contact CDR H1 with an amino acid sequence of SEQ ID NO: 13, a CDR H2 with an amino acid sequence of SEQ ID NO: 14, and a CDR H3 with an amino acid sequence of SEQ ID NO: 15 and which has a V L domain comprising a Contact CDR L1 with an amino acid sequence of SEQ ID NO: 19, a CDR L2 with an amino acid sequence of SEQ ID NO: 20, and a CDR L3 with an amino acid sequence of SEQ ID NO: 21.

9 . The isolated antibody of claim 1 , which has human framework regions.

10 . The isolated antibody of claim 1 , which comprises a human constant domain.

11 . The isolated antibody of claim 1 , wherein the antibody is an IgG, IgM, IgA or an antigen binding fragment thereof.

12 . The isolated antibody of claim 1 , wherein the antibody is a Fab′, a F(ab′)2, a F(ab′)3, a monovalent scFv, or a bivalent scFv.

13 . The isolated antibody of claim 1 , wherein the antibody is a human or humanized antibody.

14 . The isolated antibody of claim 1 , wherein the antibody is conjugated to an imaging agent, a chemotherapeutic agent, a toxin or a radionuclide.

15 . A composition comprising the isolated antibody according to claim 1 in a pharmaceutically acceptable carrier.

16 . A method for treating a subject having a cancer comprising administering an effective amount of an isolated antibody of claim 1 in a pharmaceutically acceptable composition to the subject, wherein the cancer is a breast cancer, lung cancer, head & neck cancer, prostate cancer, esophageal cancer, tracheal cancer, brain cancer, liver cancer, bladder cancer, stomach cancer, pancreatic cancer, ovarian cancer, uterine cancer, cervical cancer, testicular cancer, colon cancer, rectal cancer or skin cancer.

17 . The method of claim 16 , further comprising administering at least a second anti-cancer therapy to the subject, wherein the second anti-cancer therapy is a surgical therapy, chemotherapy, radiation therapy, cryotherapy, hormonal therapy, immunotherapy or cytokine therapy.

18 . The method of claim 17 , wherein the second anticancer therapy is durvalumab, nivolumab, pembrolizumab, avelumab, atezolizumab, cemiplimab, or ipilimumab.

19 . A method for assessing LAG3 glycosylation comprising contacting a LAG3-containing sample with an antibody according to claim 1 .

Continuity (2)
Provisional Application 62912867 · Oct 9, 2019
Related Publication 20220356248A1 · Nov 10, 2022
References Cited (304)
US 3817837A · Rubenstein et al. · 1974 [cited by applicant]
US 3842067A · Sarantakis · 1974 [cited by applicant]
US 3850752A · Schuurs et al. · 1974 [cited by applicant]
US 3862925A · Sarantakis et al. · 1975 [cited by applicant]
US 3939350A · Kronick et al. · 1976 [cited by applicant]
US 3972859A · Fujino et al. · 1976 [cited by applicant]
US 3996345A · Ullman et al. · 1976 [cited by applicant]
US 4105603A · Vale, Jr. et al. · 1978 [cited by applicant]
US 4179337A · Davis et al. · 1979 [cited by applicant]
US 4196265A · Koprowski et al. · 1980 [cited by applicant]
US 4275149A · Litman et al. · 1981 [cited by applicant]
US 4277437A · Maggio · 1981 [cited by applicant]
US 4366241A · Tom et al. · 1982 [cited by applicant]
US 4444887A · Hoffmann · 1984 [cited by applicant]
US 4469797A · Albarella · 1984 [cited by applicant]
US 4472509A · Gansow et al. · 1984 [cited by applicant]
US 4485045A · Regen · 1984 [cited by applicant]
US 4526938A · Churchill et al. · 1985 [cited by applicant]
US 4544545A · Ryan et al. · 1985 [cited by applicant]
US 4606855A · Deutsch et al. · 1986 [cited by applicant]
US 4676980A · Segal et al. · 1987 [cited by applicant]
US 4703003A · Struck · 1987 [cited by applicant]
US 4716111A · Osband et al. · 1987 [cited by applicant]
US 4742159A · Batz et al. · 1988 [cited by applicant]
US 4767720A · Lingwood · 1988 [cited by applicant]
US 4816397A · Boss et al. · 1989 [cited by applicant]
US 4816567A · Cabilly et al. · 1989 [cited by applicant]
US 4867973A · Goers et al. · 1989 [cited by applicant]
US 4870287A · Cole et al. · 1989 [cited by applicant]
US 4880078A · Inoue et al. · 1989 [cited by applicant]
US 4938948A · Ring et al. · 1990 [cited by applicant]
US 4946778A · Ladner et al. · 1990 [cited by applicant]
US 4980286A · Morgan et al. · 1990 [cited by applicant]
US 5013556A · Woodle et al. · 1991 [cited by applicant]
US 5021236A · Gries et al. · 1991 [cited by applicant]
US 5091513A · Huston et al. · 1992 [cited by applicant]
US 5128326A · Balazs et al. · 1992 [cited by applicant]
US 5164296A · Blaustein et al. · 1992 [cited by applicant]
US 5196066A · Kusuda et al. · 1993 [cited by applicant]
US 5223409A · Ladner et al. · 1993 [cited by applicant]
US 5225539A · Winter · 1993 [cited by applicant]
US 5258498A · Huston et al. · 1993 [cited by applicant]
US 5290540A · Prince et al. · 1994 [cited by applicant]
US 5403484A · Ladner et al. · 1995 [cited by applicant]
US 5413923A · Kucherlapati et al. · 1995 [cited by applicant]
US 5420253A · Emery et al. · 1995 [cited by applicant]
US 5427908A · Dower et al. · 1995 [cited by applicant]
US 5516637A · Huang et al. · 1996 [cited by applicant]
US 5530101A · Queen et al. · 1996 [cited by applicant]
US 5545806A · Lonberg et al. · 1996 [cited by applicant]
US 5565332A · Hoogenboom et al. · 1996 [cited by applicant]
US 5569825A · Lonberg et al. · 1996 [cited by applicant]
US 5571698A · Ladner et al. · 1996 [cited by applicant]
US 5580717A · Dower et al. · 1996 [cited by applicant]
US 5585089A · Queen et al. · 1996 [cited by applicant]
US 5625126A · Lonberg et al. · 1997 [cited by applicant]
US 5627052A · Schrader · 1997 [cited by applicant]
US 5633425A · Lonberg et al. · 1997 [cited by applicant]
US 5642821A · Hafliger · 1997 [cited by applicant]
US 5656434A · Terano et al. · 1997 [cited by applicant]
US 5658727A · Barbas et al. · 1997 [cited by applicant]
US 5661016A · Lonberg et al. · 1997 [cited by applicant]
US 5679377A · Bernstein et al. · 1997 [cited by applicant]
US 5698426A · Huse · 1997 [cited by applicant]
US 5733743A · Johnson et al. · 1998 [cited by applicant]
US 5739169A · Ocain et al. · 1998 [cited by applicant]
US 5750753A · Kimae et al. · 1998 [cited by applicant]
US 5760395A · Johnstone · 1998 [cited by applicant]
US 5770376A · Bagrov · 1998 [cited by applicant]
US 5780225A · Wigler et al. · 1998 [cited by applicant]
US 5789208A · Sharon · 1998 [cited by applicant]
US 5801005A · Cheever et al. · 1998 [cited by applicant]
US 5807715A · Morrison et al. · 1998 [cited by applicant]
US 5814318A · Lonberg et al. · 1998 [cited by applicant]
US 5821047A · Garrard et al. · 1998 [cited by applicant]
US 5821337A · Carter et al. · 1998 [cited by applicant]
US 5824311A · Greene et al. · 1998 [cited by applicant]
US 5830880A · Sedlacek et al. · 1998 [cited by applicant]
US 5843597A · Getz · 1998 [cited by applicant]
US 5844091A · Blaustein et al. · 1998 [cited by applicant]
US 5846945A · McCormick · 1998 [cited by applicant]
US 5855913A · Hanes et al. · 1999 [cited by applicant]
US 5858657A · Winter et al. · 1999 [cited by applicant]
US 5861155A · Lin · 1999 [cited by applicant]
US 5871907A · Winter et al. · 1999 [cited by applicant]
US 5874064A · Edwards et al. · 1999 [cited by applicant]
US 5888533A · Dunn · 1999 [cited by applicant]
US 5912015A · Bernstein et al. · 1999 [cited by applicant]
US 5916597A · Lee et al. · 1999 [cited by applicant]
US 5916771A · Hori et al. · 1999 [cited by applicant]
US 5934272A · Lloyd et al. · 1999 [cited by applicant]
US 5939598A · Kucherlapati et al. · 1999 [cited by applicant]
US 5945155A · Grill et al. · 1999 [cited by applicant]
US 5969108A · McCafferty et al. · 1999 [cited by applicant]
US 5985309A · Edwards et al. · 1999 [cited by applicant]
US 5989463A · Tracy et al. · 1999 [cited by applicant]
US 6019968A · Platz et al. · 2000 [cited by applicant]
US 6054297A · Carter et al. · 2000 [cited by applicant]
US 6165464A · Hudziak et al. · 2000 [cited by applicant]
US 6194551B1 · Idusogie et al. · 2001 [cited by applicant]
US 6277375B1 · Ward · 2001 [cited by applicant]
US 6311415B1 · Lind · 2001 [cited by applicant]
US 6331415B1 · Cabilly et al. · 2001 [cited by applicant]
US 6365157B2 · Rockwell et al. · 2002 [cited by applicant]
US 6406867B1 · Yu et al. · 2002 [cited by applicant]
US 6407213B1 · Carter et al. · 2002 [cited by applicant]
US 6639055B1 · Carter et al. · 2003 [cited by applicant]
US 6709659B1 · Lok et al. · 2004 [cited by applicant]
US 6709873B1 · Yatscoff et al. · 2004 [cited by applicant]
US 6753407B2 · Noga et al. · 2004 [cited by applicant]
US 6787153B1 · Hosokawa et al. · 2004 [cited by applicant]
US 6800738B1 · Carter et al. · 2004 [cited by applicant]
US 6814965B2 · Gao et al. · 2004 [cited by applicant]
US 6849259B2 · Haurum et al. · 2005 [cited by applicant]
US 6861572B1 · Etches et al. · 2005 [cited by applicant]
US 6875434B1 · Schenk · 2005 [cited by applicant]
US 6881557B2 · Foote · 2005 [cited by applicant]
US 6891024B2 · Marsh · 2005 [cited by applicant]
US 6946546B2 · Vaughan et al. · 2005 [cited by applicant]
US 6982323B1 · Wang et al. · 2006 [cited by applicant]
US 7407659B2 · Karumanchi et al. · 2008 [cited by applicant]
US 8178098B2 · Lahn et al. · 2012 [cited by applicant]
US 20030044407A1 · Chang et al. · 2003 [cited by applicant]
US 20050074403A1 · Kayyem et al. · 2005 [cited by applicant]
US 20050214860A1 · Zhu et al. · 2005 [cited by applicant]
US 20190105403A1 · Yoo et al. · 2019 [cited by applicant]
EP 239400A2 · 1987 [cited by applicant]
EP 519596A1 · 1992 [cited by applicant]
EP 592106A1 · 1994 [cited by applicant]
GB 2188638A · 1987 [cited by applicant]
GB 2209757A · 1989 [cited by applicant]
JP 2019518068A · 2019 [cited by applicant]
WO 8807089A1 · 1988 [cited by applicant]
WO 8907142A1 · 1989 [cited by applicant]
WO 9002809A1 · 1990 [cited by applicant]
WO 9105548A1 · 1991 [cited by applicant]
WO 9109967A1 · 1991 [cited by applicant]
WO 9110737A1 · 1991 [cited by applicant]
WO 9110741A1 · 1991 [cited by applicant]
WO 92001047A1 · 1992 [cited by applicant]
WO 9218619A1 · 1992 [cited by applicant]
WO 9219244A2 · 1992 [cited by applicant]
WO 9222324A1 · 1992 [cited by applicant]
WO 9311236A1 · 1993 [cited by applicant]
WO 9515982A2 · 1995 [cited by applicant]
WO 9520401A1 · 1995 [cited by applicant]
WO 9620698A2 · 1996 [cited by applicant]
WO 9633735A1 · 1996 [cited by applicant]
WO 9634096A1 · 1996 [cited by applicant]
WO 9732572A2 · 1997 [cited by applicant]
WO 9738731 · 1997 [cited by applicant]
WO 9744013A1 · 1997 [cited by applicant]
WO 9816654A1 · 1998 [cited by applicant]
WO 9823289A1 · 1998 [cited by applicant]
WO 9824893A2 · 1998 [cited by applicant]
WO 9831346A1 · 1998 [cited by applicant]
WO 9846645A2 · 1998 [cited by applicant]
WO 9850433A2 · 1998 [cited by applicant]
WO 9915154A1 · 1999 [cited by applicant]
WO 9920253A1 · 1999 [cited by applicant]
WO 9951642A1 · 1999 [cited by applicant]
WO 9958572A1 · 1999 [cited by applicant]
WO 9966903A2 · 1999 [cited by applicant]
WO 0042072A2 · 2000 [cited by applicant]
WO 04028564A2 · 2004 [cited by applicant]
WO 04029092A2 · 2004 [cited by applicant]
WO 04029207A2 · 2004 [cited by applicant]
WO WO2012071216A2 · 2012 [cited by examiner]
WO 2014008218A1 · 2014 [cited by applicant]
WO WO2017172517A1 · 2017 [cited by examiner]
Sela-Culang. Sela-Culang et al. The structural basis of antibody-antigen recognition. Fron. Immuno., vol. 4, Article 302, Oct. 2013. (Year: 2013). [cited by examiner]
Koenig Mutational landscape of antibody variable domains reveals a switch modulating the interdomain conformational dynamics and antigen binding. PNAS, E486-E4995, Jan. 5, 2017. (Year: 2017). [cited by examiner]
Herold. Determinants of the assembly and function of antibody variable domains. Nature Scientific Reports, 7:12276, Sep. 25, 2017. (Year: 2017). [cited by examiner]
Andrews et al. LAG3 (CD223) as a Cancer Immunotherapy Target. Immunol Rev. Mar. 2017 ; 276(1): 80-96. doi: 10.1111/imr.12519. (Year: 2017). [cited by examiner]
Abra, R M et al. “The next generation of liposome delivery systems: recent experience with tumor-targeted, sterically-stabilized immunoliposomes and active-loading gradients.” Journal of liposome research vol. 12,1-2 (2… [cited by applicant]
Al-Lazikani, B et al. “Standard conformations for the canonical structures of immunoglobulins.” Journal of molecular biology vol. 273,4 (1997): 927-48. doi:10.1006/jmbi.1997.1354. [cited by applicant]
Allen, T. M. “The use of glycolipids and hydrophilic polymers in avoiding rapid uptake of liposomes by the mononuclear phagocyte system.” Advanced drug delivery reviews 13.3 (1994): 285-309. [cited by applicant]
Alley, Stephen C et al. “Antibody-drug conjugates: targeted drug delivery for cancer.” Current opinion in chemical biology vol. 14,4 (2010): 529-37. doi:10.1016/j.cbpa.2010.06.170. [cited by applicant]
Ames, R S et al. “Conversion of murine Fabs isolated from a combinatorial phage display library to full length immunoglobulins.” Journal of immunological methods vol. 184,2 (1995): 177-86. doi:10.1016/0022-1759(95)00086… [cited by applicant]
Andrews, Lawrence P. et al., “LAG3 (CD223) as a cancer immunotherapy target”, Immunological Reviews, vol. 276, No. 1, Mar. 1, 2017 (Mar. 1, 2017), pp. 80-96, XP055717792. [cited by applicant]
Angal, S et al. “A single amino acid substitution abolishes the heterogeneity of chimeric mouse/human (IgG4) antibody.” Molecular immunology vol. 30, 1 (1993): 105-8. doi:10.1016/0161-5890(93)90432-b. [cited by applicant]
Austin-Ward ED, Villaseca C. La terapia genica y sus aplicaciones [Gene therapy and its applications]. Rev Med Chil. Jul. 1998; 126(7):838-45. Spanish. PMID: 9830778. [cited by applicant]
Barbas, C F 3rd et al. “In vitro evolution of a neutralizing human antibody to human immunodeficiency virus type 1 to enhance affinity and broaden strain cross-reactivity.” Proceedings of the National Academy of Science… [cited by applicant]
Barderas, Rodrigo et al. “Affinity maturation of antibodies assisted by in silico modeling.” Proceedings of the National Academy of Sciences of the United States of America vol. 105,26 (2008): 9029-34. doi:10.1073/pnas.… [cited by applicant]
Bendas, G. “Immunoliposomes: a promising approach to targeting cancer therapy.” BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy vol. 15,4 (2001): 215-24. doi:10.2165/00063030-200115040-00002. [cited by applicant]
Better, M et al. “ [cited by applicant]
Blume, G, and G Cevc. “Liposomes for the sustained drug release in vivo.” Biochimica et biophysica acta vol. 1029,1 (1990): 91-7. doi:10.1016/0005-2736(90)90440-y. [cited by applicant]
Bollenbach, Tobias et al. “Evolution and multilevel optimization of the genetic code.” Genome research vol. 17,4 (2007): 401-4. doi:10.1101/gr.6144007. [cited by applicant]
Brahmer, Julie R et al. “Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.” The New England journal of medicine vol. 366,26 (2012): 2455-65. doi:10.1056/NEJMoa1200694. [cited by applicant]
Brinkmann, U et al. Phage display of disulfide-stabilized Fv fragments.: Journal of immunological methods vol. 182, 1 (1995): 41-50. doi:10.1016/0022-1759(95)00016-4. [cited by applicant]
Buchwald, H et al. “Long-term, continuous intravenous heparin administration by an implantable infusion pump in ambulatory patients with recurrent venous thrombosis” Surgery vol. 88,4 (1980): 507-16. [cited by applicant]
Bukowski, R M et al. “Signal transduction abnormalities in T lymphocytes from patients with advanced renal carcinoma: clinical relevance and effects of cytokine therapy.” Clinical cancer research : an official journal o… [cited by applicant]
Burton, D R, and C F Barbas 3rd. “Human antibodies from combinatorial libraries.” Advances in immunology vol. 57 (1994): 191-280. doi:10.1016/s0065-2776(08)60674-4. [cited by applicant]
Carter, Paul J, and Peter D Senter. “Antibody-drug conjugates for cancer therapy.” Cancer journal (Sudbury, Mass.) vol. 14,3 (2008): 154-69. doi:10.1097/PPO.0b013e318172d704. [cited by applicant]
Chari, Ravi V J. “Targeted cancer therapy: conferring specificity to cytotoxic drugs.” Accounts of chemical research vol. 41,1 (2008): 98-107. doi:10.1021/ar700108g. [cited by applicant]
Chen, Y et al. “Selection and analysis of an optimized anti-VEGF antibody: crystal structure of an affinity-matured Fab in complex with antigen.” Journal of molecular biology vol. 293,4 (1999): 865-81. doi:10.1006/jmbi.… [cited by applicant]
Chothia, Cyrus, and A M Lesk. “Canonical structures for the hypervariable regions of immunoglobulins.” Journal of molecular biology vol. 196,4 (1987): 901-17. doi:10.1016/0022-2836(87)90412-8. [cited by applicant]
Christodoulides et al., Microbiology, 66(11):5329-36(1998));. [cited by applicant]
Cleek et al., Pro. Int'l. Symp. Control. Rel. Bioact. Mater. 24:853-854 (1997). [cited by applicant]
Database UniProt [Online] Sep. 18, 2019 (Sep. 18, 2019), XP002801642, retrieved from UniProt Database accession No. P18627 p. 6, middle of page. [cited by applicant]
Davidson, J A et al. “Intralesional cytokine therapy in cancer: a pilot study of GM-CSF infusion in mesothelioma.” Journal of immunotherapy (Hagerstown, Md. : 1997) vol. 21,5 (1998): 389-98. doi:10.1097/00002371-1998090… [cited by applicant]
Davies, J et al. “Expression of GnTIII in a recombinant anti-CD20 CHO production cell line: Expression of antibodies with altered glycoforms leads to an increase in ADCC through higher affinity for FC gamma RIII.” Biote… [cited by applicant]
Desmyter, A et al. “Crystal structure of a camel single-domain VH antibody fragment in complex with lysozyme.” Nature structural biology vol. 3,9 (1996): 803-11. doi:10.1038/nsb0996-803. [cited by applicant]
Dietrich, C et al. “Functional immobilization of a DNA-binding protein at a membrane interface via histidine tag and synthetic chelator lipids.” Biochemistry vol. 35,4 (1996): 1100-5. doi:10.1021/bi952305+. [cited by applicant]
Doronina, Svetlana O et al. “Development of potent monoclonal antibody auristatin conjugates for cancer therapy.” Nature biotechnology vol. 21,7 (2003): 778-84. doi:10.1038/nbt832. [cited by applicant]
Ducry, Laurent, and Bernhard Stump. “Antibody-drug conjugates: linking cytotoxic payloads to monoclonal antibodies.” Bioconjugate chemistry vol. 21,1 (2010): 5-13. doi:10.1021/bc9002019. [cited by applicant]
During, M J et al. “Controlled release of dopamine from a polymeric brain implant: in vivo characterization.” Annals of neurology vol. 25,4 (1989): 351-6. doi:10.1002/ana.410250406. [cited by applicant]
Elliott, Steve et al. “Enhancement of therapeutic protein in vivo activities through glycoengineering.” Nature biotechnology vol. 21,4 (2003): 414-21. doi:10.1038/nbt799. [cited by applicant]
Epstein et al., 1985, Proc. Natl. Acad. Sci. USA, 82: 3688. [cited by applicant]
Finlay, William J et al. “Affinity maturation of a humanized rat antibody for anti-RAGE therapy: comprehensive mutagenesis reveals a high level of mutational plasticity both inside and outside the complementarity-determ… [cited by applicant]
Gillies, S D et al. “High-level expression of chimeric antibodies using adapted cDNA variable region cassettes.” Journal of immunological methods vol. 125, 1-2 (1989): 191-202. doi:10.1016/0022-1759(89)90093-8. [cited by applicant]
Glaser, S M et al. “Antibody engineering by codon-based mutagenesis in a filamentous phage vector system.” Journal of immunology (Baltimore, Md. : 1950) vol. 149, 12 (1992): 3903-13. [cited by applicant]
Gram, H et al. “In vitro selection and affinity maturation of antibodies from a naive combinatorial immunoglobulin library.” Proceedings of the National Academy of Sciences of the United States of America vol. 89,8 (199… [cited by applicant]
Grosjean, H, and W Fiers. Preferential codon usage in prokaryotic genes: the optimal codon-anticodon interaction energy and the selective codon usage in efficiently expressed genes.: Gene vol. 18,3 (1982): 199-209. doi:… [cited by applicant]
Gustchina, Elena et al. “Affinity maturation by targeted diversification of the CDR-H2 loop of a monoclonal Fab derived from a synthetic naive human antibody library and directed against the internal trimeric coiled-coi… [cited by applicant]
Hackel, Benjamin J et al. “Stability and CDR composition biases enrich binder functionality landscapes.” Journal of molecular biology vol. 401,1 (2010): 84-96. doi:10.1016/j.jmb.2010.06.004. [cited by applicant]
Hamers-Casterman, C., T. Atarhouch, and G. Muyldermans. “Bajyama songa, E., Bendahman, N. & Hamers, R. (1993).” Nature (London) 363: 446-448. [cited by applicant]
Hanibuchi, M et al. “Therapeutic efficacy of mouse-human chimeric anti-ganglioside GM2 monoclonal antibody against multiple organ micrometastases of human lung cancer in NK cell-depleted SCID mice.” International journa… [cited by applicant]
Hansen, C B et al. “Attachment of antibodies to sterically stabilized liposomes: evaluation, comparison and optimization of coupling procedures.” Biochimica et biophysica acta vol. 1239,2 (1995): 133-44. doi:10.1016/000… [cited by applicant]
Helenius, A, and M Aebi. “Intracellular functions of N-linked glycans.” Science (New York, N.Y.) vol. 291,5512 (2001): 2364-9. doi:10.1126/science.291.5512.2364. [cited by applicant]
Hellstrand, K et al. “Histamine and cytokine therapy.” Acta oncologica (Stockholm, Sweden) vol. 37,4 (1998): 347-53. doi:10.1080/028418698430566. [cited by applicant]
Hodi, F Stephen et al. “Improved survival with ipilimumab in patients with metastatic melanoma. â€Â The New England journal of medicine vol. 363,8 (2010): 711-23. doi:10.1056/NEJMoa1003466. [cited by applicant]
Hollander, Nurit. “Immunotherapy for B-cell lymphoma: current status and prospective advances.” Frontiers in immunology 3 (2012): 3. [cited by applicant]
Honegger, A, and A Pluckthun. “Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool.” Journal of molecular biology vol. 309,3 (2001): 657-70. doi:10.1006/jmbi.2001.46… [cited by applicant]
Howard et al., 1989, J. Neurosurg. 7 1:105). [cited by applicant]
Hu, S et al. “Minibody: A novel engineered anti-carcinoembryonic antigen antibody fragment (single-chain Fv-CH3) which exhibits rapid, high-level targeting of xenografts.” Cancer research vol. 56, 13 (1996): 3055-61. [cited by applicant]
Hui, G S, and C N Hashimoto. “Pathways for potentiation of immunogenicity during adjuvant-assisted immunizations with Plasmodium falciparum major merozoite surface protein 1.” Infection and immunity vol. 66, 11 (1998): … [cited by applicant]
Huston, J S et al. “Protein engineering of single-chain Fv analogs and fusion proteins.” Methods in enzymology vol. 203 (1991): 46-88. doi:10.1016/0076-6879(91)03005-2. [cited by applicant]
Hwang, K J et al. “Hepatic uptake and degradation of unilamellar sphingomyelin/cholesterol liposomes: a kinetic study.” Proceedings of the National Academy of Sciences of the United States of America vol. 77,7 (1980): 4… [cited by applicant]
Jestin, J L, and A Kempf. “Optimization models and the structure of the genetic code.” Journal of molecular evolution vol. 69,5 (2009): 452-7. doi:10.1007/s00239-009-9287-5. [cited by applicant]
Joliot, A et al. “Antennapedia homeobox peptide regulates neural morphogenesis.” Proceedings of the National Academy of Sciences of the United States of America vol. 88,5 (1991): 1864-8. doi:10.1073/pnas.88.5.1864. [cited by applicant]
Jones, Peter T et al. “Replacing the complementarity-determining regions in a human antibody with those from a mouse.” Nature vol. 321,6069 (1986): 522-5. doi:10.1038/321522a0. [cited by applicant]
Kabat, E A et al. “Unusual distributions of amino acids in complementarity-determining (hypervariable) segments of heavy and light chains of immunoglobulins and their possible roles in specificity of antibody-combining … [cited by applicant]
Kabat, E A. “The structural basis of antibody complementarity.” Advances in protein chemistry vol. 32 (1978): 1-75. [cited by applicant]
Katoh, Kazutaka et al. “MAFFT: a novel method for rapid multiple sequence alignment based on fast Fourier transform.” Nucleic acids research vol. 30, 14 (2002): 3059-66. doi:10.1093/nar/gkf436. [cited by applicant]
Kettleborough, C A et al. “Isolation of tumor cell-specific single-chain Fv from immunized mice using phage-antibody libraries and the re-construction of whole antibodies from these antibody fragments.” European journal… [cited by applicant]
Kisielow, Malgorzata “Lymphocyte Activation Gene-3—the expression and function in the immune system”, Jan. 1, 2006 (Jan. 1, 2006), pp. 1-123, XP055765696. [cited by applicant]
Klibanov, A L et al. “Activity of amphipathic poly(ethylene glycol) 5000 to prolong the circulation time of liposomes depends on the liposome size and is unfavorable for immunoliposome binding to target.” Biochimica et … [cited by applicant]
Klibanov, A L et al. “Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes.” FEBS letters vol. 268, 1 (1990): 235-7. doi:10.1016/0014-5793(90)81016-h. [cited by applicant]
Knappik, A, and A Pluckthun. “An improved affinity tag based on the FLAG peptide for the detection and purification of recombinant antibody fragments.” BioTechniques vol. 17,4 (1994): 754-61. [cited by applicant]
Krause, J. C. et al., MBio. 2(1) pii: e00345-10. doi: 10.1128/mBio.00345-10(2011). [cited by applicant]
Kuan, Chien-Tsun, et al. “Affinity-matured anti-glycoprotein NMB recombinant immunotoxins targeting malignant gliomas and melanomas.” International journal of cancer 129.1 (2011): 111-121. [cited by applicant]
Kurland, C G, and M Ehrenberg. “Optimization of translation accuracy.” Progress in nucleic acid research and molecular biology vol. 31 (1984): 191-219. doi:10.1016/s0079-6603(08)60378-5. [cited by applicant]
Lam, X. M., E. T. Duenas, and J. L. Cleland. “Microencapsulation of recombinant humanized monoclonal antibody for local delivery.” Proceedings of the 24th International Symposium on Controlled Release of Bioactive Mater… [cited by applicant]
Langer, Robert, and Nikolaos Peppas. “Chemical and physical structure of polymers as carriers for controlled release of bioactive agents: a review.” Journal of Macromolecular Science-Reviews in Macromolecular Chemistry … [cited by applicant]
Lefranc, Marie-Paule et al. “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains.” Developmental and comparative immunology vol. 27,1 (2003): 55-77. doi:10.101… [cited by applicant]
Levy, R J et al. “Inhibition of calcification of bioprosthetic heart valves by local controlled-release diphosphonate.” Science (New York, N.Y.) vol. 228,4696 (1985): 190-2. doi:10.1126/science.3919445. [cited by applicant]
Lichtenegger, Felix S. et al., “Targeting LAG-3 and PD-1 to Enhance T Cell Activation by Antigen-Presenting Cells”, Frontiers in Immunology, vol. 9, Feb. 27, 2018 (Feb. 27, 2018), XP055766274. [cited by applicant]
Litzinger, D C et al. “Effect of liposome size on the circulation time and intraorgan distribution of amphipathic poly (ethylene glycol)-containing liposomes.” Biochimica et biophysica acta vol. 1190,1 (1994): 99-107. d… [cited by applicant]
Lonberg, N, and D Huszar. Human antibodies from transgenic mice.: International reviews of immunology vol. 13,1 (1995): 65-93. doi:10.3109/08830189509061738. [cited by applicant]
Long, Long et al. “The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy.” Genes & cancer vol. 9,5-6 (2018): 176-189. doi:10.18632/genesandcancer.180. [cited by applicant]
Loughrey, H et al. “A non-covalent method of attaching antibodies to liposomes.” Biochimica et biophysica acta vol. 901,1 (1987): 157-60. doi:10.1016/0005-2736(87)90267-7. [cited by applicant]
Marchler-Bauer, Aron et al. “CDD: a Conserved Domain Database for the functional annotation of proteins.” Nucleic acids research vol. 39, Database issue (2011): D225-9. doi:10.1093/nar/gkq1189. [cited by applicant]
Marks, J D et al. “By-passing immunization: building high affinity human antibodies by chain shuffling.” Bio/technology (Nature Publishing Company) vol. 10,7 (1992): 779-83. doi:10.1038/nbt0792-779. [cited by applicant]
Martin et al., 1981, Biochemistry, 20: 4429-38. [cited by applicant]
Martin, A C, and J M Thornton. “Structural families in loops of homologous proteins: automatic classification, modelling and application to antibodies.” Journal of molecular biology vol. 263,5 (1996): 800-15. doi:10.100… [cited by applicant]
Martin, F J, and D Papahadjopoulos. “Irreversible coupling of immunoglobulin fragments to preformed vesicles. An improved method for liposome targeting.” The Journal of biological chemistry vol. 257, 1 (1982): 286-8. [cited by applicant]
Maruyama, K et al. “Effect of molecular weight in amphipathic polyethyleneglycol on prolonging the circulation time of large unilamellar liposomes.” Chemical & pharmaceutical bulletin vol. 39,6 (1991): 1620-2. doi:10.12… [cited by applicant]
Maruyama, K. “In vivo targeting by liposomes.” Biological & pharmaceutical bulletin vol. 23,7 (2000): 791-9. doi:10.1248/bpb.23.791. [cited by applicant]
Montgomery, Donna L et al. “Affinity maturation and characterization of a human monoclonal antibody against HIV-1 gp41.” mAbs vol. 1,5 (2009): 462-74. doi:10.4161/mabs.1.5.9214. [cited by applicant]
Morea, V et al. “Antibody modeling: implications for engineering and design.” Methods (San Diego, Calif.) vol. 20,3 (2000): 267-79. doi:10.1006/meth.1999.0921. [cited by applicant]
Morrison, S L et al. “Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains.” Proceedings of the National Academy of Sciences of the United States of America vol. 81,21 (198… [cited by applicant]
Morrison, S L. “Transfectomas provide novel chimeric antibodies.” Science (New York, N.Y.) vol. 229,4719 (1985): 1202-7. doi:10.1126/science.3929380. [cited by applicant]
Mueller, J P et al. “Humanized porcine VCAM-specific monoclonal antibodies with chimeric IgG2/G4 constant regions block human leukocyte binding to porcine endothelial cells.” Molecular immunology vol. 34,6 (1997): 441-5… [cited by applicant]
Mullinax, R L et al. “Expression of a heterodimeric Fab antibody protein in one cloning step.” BioTechniques vol. 12,6 (1992): 864-9. [cited by applicant]
Murali, R et al. “Antibody like peptidomimetics as large scale immunodetection probes.” Cellular and molecular biology (Noisy-le-Grand, France) vol. 49,2 (2003): 209-16. [cited by applicant]
Ning, S et al. “Intratumoral radioimmunotherapy of a human colon cancer xenograft using a sustained-release gel.” Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology vol. 3… [cited by applicant]
Oroudjev et al., Mol. Cancer Ther., 10L2700-2713 (2010)). [cited by applicant]
Padlan, E A. “A possible procedure for reducing the immunogenicity of antibody variable domains while preserving their ligand-binding properties.” Molecular immunology vol. 28,4-5 (1991): 489-98. doi:10.1016/0161-5890(9… [cited by applicant]
Persic, L et al. “An integrated vector system for the eukaryotic expression of antibodies or their fragments after selection from phage display libraries.” Gene vol. 187,1 (1997): 9-18. doi:10.1016/s0378-1119(96)00628-2. [cited by applicant]
Pluckthun, A, and A Skerra. “Expression of functional antibody Fv and Fab fragments in [cited by applicant]
Presta, Leonard G. “Antibody engineering.”  Current Opinion in Structural Biology 2.4 (1992): 593-596. [cited by applicant]
Presta, Leonard G. “Molecular engineering and design of therapeutic antibodies.” Current opinion in immunology vol. 20,4 (2008): 460-70. doi:10.1016/j.coi.2008.06.012. [cited by applicant]
Qin, X Q et al. “Interferon-beta gene therapy inhibits tumor formation and causes regression of established tumors in immune-deficient mice.” Proceedings of the National Academy of Sciences of the United States of Ameri… [cited by applicant]
Riechmann et al., Nature, 332:323-329 (1988). [cited by applicant]
Roguska, M A et al. “Humanization of murine monoclonal antibodies through variable domain resurfacing.” Proceedings of the National Academy of Sciences of the United States of AmericaA vol. 91,3 (1994): 969-73. doi:10.1… [cited by applicant]
Routledge, E G et al. “The effect of aglycosylation on the immunogenicity of a humanized therapeutic CD3 monoclonal antibody.” Transplantation vol. 60,8 (1995): 847-53. [cited by applicant]
Sali, A, and T L Blundell. “Comparative protein modelling by satisfaction of spatial restraints.” Journal of molecular biology vol. 234,3 (1993): 779-815. doi:10.1006/jmbi.1993.1626. [cited by applicant]
Saudek, C D et al. “A preliminary trial of the programmable implantable medication system for insulin delivery.” The New England journal of medicine vol. 321,9 (1989): 574-9. doi:10.1056/NEJM198908313210904. [cited by applicant]
Sawai, H et al. “Direct production of the Fab fragment derived from the sperm immobilizing antibody using polymerase chain reaction and cDNA expression vectors.” American journal of reproductive immunology (New York, N.… [cited by applicant]
Schier, R et al. “Identification of functional and structural amino-acid residues by parsimonious mutagenesis.” Gene vol. 169,2 (1996): 147-55. doi:10.1016/0378-1119(95)00821-7. [cited by applicant]
Schier, R et al. “Isolation of picomolar affinity anti-c-erbB-2 single-chain Fv by molecular evolution of the complementarity determining regions in the center of the antibody binding site.” Journal of molecular biology… [cited by applicant]
Schwarz, Flavio, and Markus Aebi. “Mechanisms and principles of N-linked protein glycosylation.” Current opinion in structural biology vol. 21,5 (2011): 576-82. doi:10.1016/j.sbi.2011.08.005. [cited by applicant]
Senter, Peter D. “Potent antibody drug conjugates for cancer therapy.” Current opinion in chemical biology vol. 13,3 (2009): 235-44. doi:10.1016/j.cbpa.2009.03.023. [cited by applicant]
Shields, Robert L et al. “Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma RIII and antibody-dependent cellular toxicity.” The Journal of biological chemistry vol. 277,30 (2002): 2… [cited by applicant]
Shu, L et al. “Secretion of a single-gene-encoded immunoglobulin from myeloma cells.” Proceedings of the National Academy of Sciences of the United States of America vol. 90,17 (1993): 7995-9. doi:10.1073/pnas.90.17.799… [cited by applicant]
Skerra, A, and A Pluckthun. “Assembly of a functional immunoglobulin Fv fragment in [cited by applicant]
Song, Y K et al. “Antibody mediated lung targeting of long-circulating emulsions.” PDA journal of pharmaceutical science and technology vol. 50,6 (1996): 372-7. [cited by applicant]
Steidl, Stefan et al. “In vitro affinity maturation of human GM-CSF antibodies by targeted CDR-diversification.” Molecular immunology vol. 46, 1 (2008): 135-44. doi:10.1016/j.molimm.2008.07.013. [cited by applicant]
Stemmer, W P. “Rapid evolution of a protein in vitro by DNA shuffling.” Nature vol. 370,6488 (1994): 389-91. doi:10.1038/370389a0. [cited by applicant]
Studnicka, G M et al. “Human-engineered monoclonal antibodies retain full specific binding activity by preserving non-CDR complementarity-modulating residues.” Protein engineering vol. 7,6 (1994): 805-14. doi:10.1093/pr… [cited by applicant]
Swann, Patrick G et al. “Considerations for the development of therapeutic monoclonal antibodies.” Current opinion in immunology vol. 20,4 (2008): 493-9. doi:10.1016/j.coi.2008.05.013. [cited by applicant]
Tao, M H, and S L Morrison. “Studies of aglycosylated chimeric mouse-human IgG. Role of carbohydrate in the structure and effector functions mediated by the human IgG constant region.” Journal of immunology (Baltimore, … [cited by applicant]
Taylor, L D et al. “A transgenic mouse that expresses a diversity of human sequence heavy and light chain immunoglobulins.” Nucleic acids research vol. 20,23 (1992): 6287-95. doi:10.1093/nar/20.23.6287. [cited by applicant]
Teicher, B A. “Antibody-drug conjugate targets.” Current cancer drug targets vol. 9,8 (2009): 982-1004. doi:10.2174/156800909790192365. [cited by applicant]
Topalian, Suzanne L et al. “Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.” The New England journal of medicine vol. 366,26 (2012): 2443-54. doi:10.1056/NEJMoa1200690. [cited by applicant]
Torchilin, Vladimir P. “How do polymers prolong circulation time of liposomes ?. ” Journal of Liposome Research 6.1 (1996): 99-116. [cited by applicant]
Vingerhoeds, M H et al. “Immunoliposomes in vivo.” ImmunoMethods vol. 4,3 (1994): 259-72. doi:10.1006/immu. 1994.1028. [cited by applicant]
Wallick, S C et al. “Glycosylation of a VH residue of a monoclonal antibody against alpha (1—6) dextran increases its affinity for antigen.” The Journal of experimental medicine vol. 168,3 (1988): 1099-109. doi:10.1084/… [cited by applicant]
Wilson, I A et al. “The structure of an antigenic determinant in a protein.” Cell vol. 37,3 (1984): 767-78. doi:10.1016/0092-8674(84)90412-4. [cited by applicant]
Wohlgemuth, Ingo et al. “Evolutionary optimization of speed and accuracy of decoding on the ribosome.” Philosophical transactions of the Royal Society of London. Series B, Biological sciences vol. 366, 1580 (2011): 2979… [cited by applicant]
Wu, GY, and C H Wu. “Receptor-mediated in vitro gene transformation by a soluble DNA carrier system.” The Journal of biological chemistry vol. 262, 10 (1987): 4429-32. [cited by applicant]
Wu, H et al. “Stepwise in vitro affinity maturation of Vitaxin, an alphav beta3-specific humanized mAb.” Proceedings of the National Academy of Sciences of the United States of America vol. 95, 11 (1998): 6037-42. doi:1… [cited by applicant]
Yelton, D E et al. “Affinity maturation of the BR96 anti-carcinoma antibody by codon-based mutagenesis.” Journal of immunology (Baltimore, Md. : 1950)Â vol. 155,4 (1995): 1994-2004. [cited by applicant]