Granted Patent
B2
US 12,280,120 · App. 17/535,451 · Granted Apr 22, 2025
Tumor-specific cleavable linkers
Inventors:
Raphael Rozenfeld (Swampscott, MA); Ugur Eskiocak (Somerville, MA); Huawei Qiu (Westborough, MA); Parker Johnson (Allston, MA); Kurt Allen Jenkins (Weymouth, MA); Magali Pederzoli-Ribeil (Cambridge, MA); Dheeraj Singh Tomar (Dorchester, MA); Rebekah Kay O'Donnell (Brookline, MA)
Assignee:
Xilio Development, Inc.
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Abstract
The present disclosure provides tumor-specific cleavable linkers and their use in drugs and prodrugs for delivering therapeutics to a tumor cell environment. The present disclosure also provides cleavage products of said drugs and prodrugs, and methods related to the use of the same.
Claims (14)
1. A masked interleukin 12 (IL-12) cytokine comprising:
a first polypeptide chain comprising a first Fc domain, and a masking moiety comprising the amino acid sequence of SEQ ID NO: 220;
a second polypeptide chain comprising a second Fc domain, a first linker comprising a proteolytically cleavable peptide of SEQ ID NO: 249, and an IL-12 cytokine comprising an IL-12p40 polypeptide linked to an IL-12p35 polypeptide; and
wherein the IL-12p40 polypeptide comprises the amino acid sequence of SEQ ID NO: 208 and the IL-12p35 polypeptide comprises the amino acid sequence of SEQ ID NO: 209.
2. The masked IL-12 cytokine of claim 1 , wherein the IL-12p40 polypeptide is linked to the IL-12p35 polypeptide via a second linker comprising the amino acid sequence of SEQ ID NO: 116.
3. The masked IL-12 cytokine of claim 1 , wherein the first Fc domain comprises the amino acid sequence of SEQ ID NO: 8.
4. The masked IL-12 cytokine of claim 3 , wherein the second Fc domain comprises the amino acid sequence of SEQ ID NO: 11.
5. The masked IL-12 cytokine of claim 1 , wherein the first Fc domain comprises the amino acid sequence of SEQ ID NO: 9.
6. The masked IL-12 cytokine of claim 5 , wherein the second Fc domain comprises the amino acid sequence of SEQ ID NO: 12.
7. The masked IL-12 cytokine of claim 1 , wherein the first linker comprises the amino acid sequence of SEQ ID NO: 115.
8. The masked IL-12 cytokine of claim 1 , wherein the first polypeptide chain comprises a non-cleavable linker between the first Fc domain and the masking moiety, and wherein the non-cleavable linker comprises the amino acid sequence of SEQ ID NO: 35.
9. The masked IL-12 cytokine of claim 1 , wherein the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 192.
10. The masked IL-12 cytokine of claim 1 , wherein the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 195.
11. A masked IL-12 cytokine comprising a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 192 and a second polypeptide chain comprising the amino acid sequence of SEQ ID NO: 195.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Sep 13, 2022
From: ROZENFELD, RAPHAEL; ESKIOCAK, UGUR; QIU, HUAWEI; JOHNSON, PARKER; JENKINS, KURT ALLEN; PEDERZOLI-RIBEIL, MAGALI; TOMAR, DHEERAJ SINGH; O'DONNELL, REBEKAH KAY
To: XILIO DEVELOPMENT, INC.
Reel/Frame 061074/0644 →
Continuity (3)
Provisional Application
63253090
· Oct 6, 2021
Provisional Application
63118585
· Nov 25, 2020
References Cited (339)
US RE30985E
· Cartaya
· 1982
[cited by applicant]
US 4419446A
· Howley et al.
· 1983
[cited by applicant]
US 4560655A
· Baker
· 1985
[cited by applicant]
US 4601978A
· Karin
· 1986
[cited by applicant]
US 4657866A
· Kumar
· 1987
[cited by applicant]
US 4676980A
· Segal et al.
· 1987
[cited by applicant]
US 4767704A
· Cleveland
· 1988
[cited by applicant]
US 4816567A
· Cabilly et al.
· 1989
[cited by applicant]
US 4927762A
· Darfler
· 1990
[cited by applicant]
US 4965199A
· Capon et al.
· 1990
[cited by applicant]
US 5122464A
· Wilson et al.
· 1992
[cited by applicant]
US 5122469A
· Mather et al.
· 1992
[cited by applicant]
US 5208020A
· Chari et al.
· 1993
[cited by applicant]
US 5264365A
· Georgiou
· 1993
[cited by applicant]
US 5416064A
· Chari et al.
· 1995
[cited by applicant]
US 5508192A
· Georgiou et al.
· 1996
[cited by applicant]
US 5571894A
· Weis et al.
· 1996
[cited by applicant]
US 5587458A
· King et al.
· 1996
[cited by applicant]
US 5624821A
· Winter et al.
· 1997
[cited by applicant]
US 5635483A
· Pettit et al.
· 1997
[cited by applicant]
US 5639635A
· Joly et al.
· 1997
[cited by applicant]
US 5641870A
· Rinderknecht et al.
· 1997
[cited by applicant]
US 5648237A
· Carter et al.
· 1997
[cited by applicant]
US 5648260A
· Winter et al.
· 1997
[cited by applicant]
US 5650150A
· Gillies
· 1997
[cited by applicant]
US 5712374A
· Kunstmann et al.
· 1998
[cited by applicant]
US 5714586A
· Kunstmann et al.
· 1998
[cited by applicant]
US 5739277A
· Presta et al.
· 1998
[cited by applicant]
US 5767285A
· Hamann et al.
· 1998
[cited by applicant]
US 5770701A
· McGahren et al.
· 1998
[cited by applicant]
US 5770710A
· McGahren et al.
· 1998
[cited by applicant]
US 5773001A
· Hamann et al.
· 1998
[cited by applicant]
US 5780588A
· Pettit et al.
· 1998
[cited by applicant]
US 5834597A
· Tso et al.
· 1998
[cited by applicant]
US 5869046A
· Presta et al.
· 1999
[cited by applicant]
US 5877296A
· Hamann et al.
· 1999
[cited by applicant]
US 5891693A
· Bebbington et al.
· 1999
[cited by applicant]
US 5939598A
· Kucherlapati et al.
· 1999
[cited by applicant]
US 6027888A
· Georgiou et al.
· 2000
[cited by applicant]
US 6075181A
· Kucherlapati et al.
· 2000
[cited by applicant]
US 6083715A
· Georgiou et al.
· 2000
[cited by applicant]
US 6114598A
· Kucherlapati et al.
· 2000
[cited by applicant]
US 6150584A
· Kucherlapati et al.
· 2000
[cited by applicant]
US 6162963A
· Kucherlapati et al.
· 2000
[cited by applicant]
US 6165745A
· Ward et al.
· 2000
[cited by applicant]
US 6194551B1
· Idusogie et al.
· 2001
[cited by applicant]
US 6248516B1
· Winter et al.
· 2001
[cited by applicant]
US 6602684B1
· Umana et al.
· 2003
[cited by applicant]
US 6630579B2
· Chari et al.
· 2003
[cited by applicant]
US 6821505B2
· Ward et al.
· 2004
[cited by applicant]
US 6942853B2
· Chernajovsky et al.
· 2005
[cited by applicant]
US 7498298B2
· Doronina et al.
· 2009
[cited by applicant]
US 8399219B2
· Stagliano et al.
· 2013
[cited by applicant]
US 8507222B2
· Wong et al.
· 2013
[cited by applicant]
US 9206243B2
· Monzon et al.
· 2015
[cited by applicant]
US 9428573B2
· Wong et al.
· 2016
[cited by applicant]
US 9975937B2
· Pavlakis et al.
· 2018
[cited by applicant]
US 20030157108A1
· Presta et al.
· 2003
[cited by applicant]
US 20040053829A1
· Pfizenmaier et al.
· 2004
[cited by applicant]
US 20040093621A1
· Shitara et al.
· 2004
[cited by applicant]
US 20040110704A1
· Yamane et al.
· 2004
[cited by applicant]
US 20040132140A1
· Satoh et al.
· 2004
[cited by applicant]
US 20060236411A1
· Dreher et al.
· 2006
[cited by applicant]
US 20070048282A1
· Rosen et al.
· 2007
[cited by applicant]
US 20070269422A1
· Beirnaert et al.
· 2007
[cited by applicant]
US 20140302037A1
· Borges et al.
· 2014
[cited by applicant]
US 20160152686A1
· Camphausen et al.
· 2016
[cited by applicant]
US 20190391152A1
· Abrignani et al.
· 2019
[cited by applicant]
US 20210024631A1
· Kley et al.
· 2021
[cited by applicant]
US 20210061871A1
· Niazi et al.
· 2021
[cited by applicant]
US 20210115102A1
· Winston et al.
· 2021
[cited by applicant]
US 20210221864A1
· Williams et al.
· 2021
[cited by applicant]
US 20210238308A1
· Ikawa et al.
· 2021
[cited by applicant]
US 20210260163A1
· Yu et al.
· 2021
[cited by applicant]
US 20220002370A1
· Karow et al.
· 2022
[cited by applicant]
US 20220025050A1
· Poirier et al.
· 2022
[cited by applicant]
CN 103002913A
· 2013
[cited by applicant]
CN 105229031A
· 2016
[cited by applicant]
CN 108218993A
· 2018
[cited by applicant]
EP 0425235B1
· 1996
[cited by applicant]
EP 2639241A2
· 2019
[cited by applicant]
EP 3093295B1
· 2020
[cited by applicant]
EP 3740501A1
· 2020
[cited by applicant]
EP 3762406A2
· 2021
[cited by applicant]
EP 3773674A1
· 2021
[cited by applicant]
EP 3792277A1
· 2021
[cited by applicant]
EP 3810171A1
· 2021
[cited by applicant]
JP S63203626A
· 1988
[cited by applicant]
JP 2004508828A
· 2004
[cited by applicant]
JP 2021530243A
· 2021
[cited by applicant]
WO WO8700195A1
· 1987
[cited by applicant]
WO WO9003430A1
· 1990
[cited by applicant]
WO WO9101743A1
· 1991
[cited by applicant]
WO 9208495A1
· 1992
[cited by applicant]
WO WO9308829A1
· 1993
[cited by applicant]
WO WO9316185A2
· 1993
[cited by applicant]
WO WO9411026A2
· 1994
[cited by applicant]
WO WO9429351A2
· 1994
[cited by applicant]
WO WO9627011A1
· 1996
[cited by applicant]
WO WO9730087A1
· 1997
[cited by applicant]
WO WO9858964A1
· 1998
[cited by applicant]
WO WO9922764A1
· 1999
[cited by applicant]
WO 9927011A2
· 1999
[cited by applicant]
WO WO9951642A1
· 1999
[cited by applicant]
WO 0042072A2
· 2000
[cited by applicant]
WO WO0061739A1
· 2000
[cited by applicant]
WO 0129246A1
· 2001
[cited by applicant]
WO WO0179271A1
· 2001
[cited by applicant]
WO WO0243478A2
· 2002
[cited by applicant]
WO WO02076489A1
· 2002
[cited by applicant]
WO WO03011878A2
· 2003
[cited by applicant]
WO WO0359934A2
· 2003
[cited by applicant]
WO WO03084570A1
· 2003
[cited by applicant]
WO WO03085119A1
· 2003
[cited by applicant]
WO WO2004041865A2
· 2004
[cited by applicant]
WO WO2004056312A2
· 2004
[cited by applicant]
WO WO2005035586A1
· 2005
[cited by applicant]
WO WO2005035778A1
· 2005
[cited by applicant]
WO WO2005053742A1
· 2005
[cited by applicant]
WO WO2006106905A1
· 2006
[cited by applicant]
WO 2006133148A2
· 2006
[cited by applicant]
WO 2011100786A1
· 2011
[cited by applicant]
WO WO2011124718A1
· 2011
[cited by applicant]
WO WO2012059486A1
· 2012
[cited by applicant]
WO 2012107417A1
· 2012
[cited by applicant]
WO 2016154675A1
· 2016
[cited by applicant]
WO WO2016200645A1
· 2016
[cited by applicant]
WO 2017127514A1
· 2017
[cited by applicant]
WO 2017165464A1
· 2017
[cited by applicant]
WO WO2018071918A1
· 2018
[cited by applicant]
WO 2018151868A2
· 2018
[cited by applicant]
WO 2018184964A1
· 2018
[cited by applicant]
WO 2018184965A1
· 2018
[cited by applicant]
WO 2019129053A1
· 2019
[cited by applicant]
WO 2019166946A1
· 2019
[cited by applicant]
WO WO2019173832A2
· 2019
[cited by applicant]
WO 2019191295A1
· 2019
[cited by applicant]
WO WO2019214757A1
· 2019
[cited by applicant]
WO WO2019222294A1
· 2019
[cited by applicant]
WO WO2019222295A1
· 2019
[cited by applicant]
WO 2019246379A1
· 2019
[cited by applicant]
WO WO2019246392A1
· 2019
[cited by applicant]
WO 2020023702A1
· 2020
[cited by applicant]
WO 2020041758A1
· 2020
[cited by applicant]
WO 2020047299A1
· 2020
[cited by applicant]
WO 2020086758A1
· 2020
[cited by applicant]
WO WO2020069398A1
· 2020
[cited by applicant]
WO 2020088459A1
· 2020
[cited by applicant]
WO 2020123980A1
· 2020
[cited by applicant]
WO 2020146221A1
· 2020
[cited by applicant]
WO 2020232305A1
· 2020
[cited by applicant]
WO 2020259536A1
· 2020
[cited by applicant]
WO WO2020252264A1
· 2020
[cited by applicant]
WO 2021001289A1
· 2021
[cited by applicant]
WO 2021016640A1
· 2021
[cited by applicant]
WO WO2021016599A1
· 2021
[cited by applicant]
WO 2021030633A1
· 2021
[cited by applicant]
WO 2021035188A1
· 2021
[cited by applicant]
WO WO2021030483A1
· 2021
[cited by applicant]
WO 2021054867A1
· 2021
[cited by applicant]
WO 2021062406A1
· 2021
[cited by applicant]
WO 2021092719A1
· 2021
[cited by applicant]
WO 2021119429A1
· 2021
[cited by applicant]
WO 2021119516A1
· 2021
[cited by applicant]
WO 2021127487A2
· 2021
[cited by applicant]
WO 2021127495A1
· 2021
[cited by applicant]
WO 2021142471A1
· 2021
[cited by applicant]
WO 2021142476A1
· 2021
[cited by applicant]
WO 2021149697A1
· 2021
[cited by applicant]
WO 2021150936A1
· 2021
[cited by applicant]
WO 2021189139A1
· 2021
[cited by applicant]
WO 2021202673A2
· 2021
[cited by applicant]
WO 2021202675A1
· 2021
[cited by applicant]
WO 2021202678A1
· 2021
[cited by applicant]
WO 2021216916A1
· 2021
[cited by applicant]
WO WO2022115865A2
· 2022
[cited by applicant]
WO 2024015960A1
· 2024
[cited by applicant]
Diguanylate cyclase [
[cited by examiner]
Proteolytically cleavable peptide linker, from https://web.expasy.org/cgi-bin/peptide_cutter/peptidecutter.pl, accessed 2024, pp. 1-2.
[cited by examiner]
Diguanylate cyclase, from https://web.archive.org/web/20171107063802/https://enzyme.expasy.org/EC/2.7.7.65, 2017, pp. 1-2.
[cited by examiner]
Berry et al., Valine, Isoleucine, and Leucine a New Treatment for Phenylketonuria, AJDC, 1990, 144, pp. 539-543.
[cited by examiner]
Zaman et al, Current strategies in extending half-lives of therapeutic proteins, Journal of Controlled Release, 2019, 301, pp. 176-189.
[cited by examiner]
International Search Report for PCT/US2021/025107 dated Jul. 21, 2021 (4 pages).
[cited by applicant]
International Search Report for PCT/US2023/014128 dated Aug. 21, 2023 (11 pages).
[cited by applicant]
International Search Report for PCT/US2021/025100 dated Sep. 24, 2021 (6 pages).
[cited by applicant]
International Search Report for PCT/US2023/070206 dated Oct. 18, 2023 (7 pages).
[cited by applicant]
International Search Report for PCT/US2021/025103 dated Aug. 18, 2021 (7 pages).
[cited by applicant]
“Remington: The Science and Practice of Pharmacy”, Gennaro (Ed.), 20th Edition, 2000, Lippincott Williams & Wilkins, Philadelphia, PA.
[cited by applicant]
Adams, Gill , et al., “Targeting cytokines to inflammation sites”, Nature Biotechnology, vol. 21, No. 11, Nov. 2003, pp. 1314-1320, DOI: 10.1038/nbt888 (7 pages).
[cited by applicant]
Berge, Stephen M., et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Sciences, vol. 66, No. 1, Jan. 1977, pp. 1-19, DOI: 10.1002/jps.2600660104, (19 pages).
[cited by applicant]
Bothmann, Hendrick , et al., “The Periplasmic
[cited by applicant]
Brodeur, Bernard R., et al., “Mouse-Human Myeloma Partners for the Production of Heterohybridomas”, Monoclonal Antibody Production Techniques and Applications, Ch. 4, 1987, pp. 51-63 (13 pages).
[cited by applicant]
Cameron, Mark J., et al., “Cytokines, Chemokines and Their Receptors”, Madame Curie Bioscience Database [Internet], Austin (TX): Landes Bioscience; 2000-2013 (25 pages).
[cited by applicant]
Chen, Xiaoying , et al., “Fusion Protein Linkers: Property, Design and Functionality”, Advanced Drug Delivery Reviews, vol. 65, No. 10, Oct. 15, 2013, pp. 1357-1369, DOI: 10.1016/j.addr.2012.09.039, (32 pages).
[cited by applicant]
Hsu, Eric J., et al., “A cytokine receptor-masked IL2 prodrug selectively activates tumor-infiltrating lymphocytes for potent antitumor therapy”, Nature Communications, vol. 12, 2021, pp. 2768, DOI: 10.1038/s41467-021-2…
[cited by applicant]
Kuen, Martin Matthias, “Antibody masked cytokines as new approach in targeted tumor therapy”, Doctoral Dissertation, Aug. 2015 (126 pages).
[cited by applicant]
Reichmann, Lutz , et al., “Reshaping human antibodies for therapy”, Nature, vol. 332, 1988, pp. 323-327, DOI: 10.1038/332323a0 (5 pages).
[cited by applicant]
Wüest, Thomas , et al., “TNF-Selectokine: a novel prodrug generated for tumor targeting and site-specific activation of tumor necrosis factor”, Oncogene, vol. 21, 2002, pp. 4257-4265 (9 pages).
[cited by applicant]
Ha, Ji-Hee et al., “Immunoglobulin Fc Heterodimer Platform Technology: From Design to Applications in Therapeutic Antibodies and Proteins”, Frontiers in Immunology, vol. 7, No. 394, Oct. 6, 2016.
[cited by applicant]
Skrombolas, D. et al., “Development of an Interleukin-12 Fusion Protein That Is Activated by Cleavage with Matrix Metalloproteinase 9”, Journal of Interferon & Cytokine Research, vol. 39, No. 4, Apr. 1, 2019, pp. 233-24…
[cited by applicant]
Arie et al. “Chaperone function of FkpA, a heat shock prolyl isomerase, in the periplasm of
[cited by applicant]
Atwell et al., “Stable heterodimers from remodeling the domain interface of a homodimer using a phage display library,” J. Mol. Biol. (1997) 270(1): 26-35.
[cited by applicant]
Bachmann, Cellular and Molecular Biology, vol. 2 (Washington, D.C.: American Society for Microbiology, 1987), pp. 1190-1219.
[cited by applicant]
Barnes et al., “Methods for growth of cultured cells in serum-free medium,” Anal. Biochem. 102: 255 (1980). 16 pages.
[cited by applicant]
Bass et al., “Hormone phage: an enrichment method for variant proteins with altered binding properties,” Proteins, 8: 309-314 (1990).
[cited by applicant]
Bernett et al., “Potency-reduced IL15/IL15Rα heterodimeric Fc-fusions display enhanced in vivo activity through increased exposure,” Xencor, AACR (2018) Abstract #5565. 1 page.
[cited by applicant]
Boerner et al., “Production of antigen-specific human monoclonal antibodies from in vitro-primed human splenocytes,” J. Immunol., 147: 86 (1991). 10 pages.
[cited by applicant]
Bothmann and Pluckthun. “Improving Expression of scFv Fragments by Coexpression of Periplasmic Chaperones,” (2000) J. Biol. Chem. 275: 17100-17105.
[cited by applicant]
Brennan et al., “Preparation of bispecific antibodies by chemical recombination of monoclonal immunoglobulin G1 fragments,” Science, 229: 81(1985). 3 pages.
[cited by applicant]
Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 Marcel Dekker, Inc., New York, 1987.
[cited by applicant]
Caescu et al., “Active site determinants of substrate recognition by the metalloproteinases TACE and ADAM10,” Biochem. J. (2010) 424 (1): 79-88.
[cited by applicant]
Carter et al., “High level
[cited by applicant]
Carter et al. (2001), “Bispecific human IgG by design,” J. Immunol. Methods, 248: 7-15.
[cited by applicant]
Chapman et al. (1999) “Therapeutic antibody fragments with prolonged in vivo half-lives,” Nature Biotechnol., 17: 780-783.
[cited by applicant]
Chari et al., “Immunoconjugates containing novel maytansinoids: promising anticancer drugs,” Cancer Res. 52:127-131 (1992).
[cited by applicant]
Chen et al. (1999) “Chaperone activity of DsbC,” J. Biol. Chem. 274:19601-19605.
[cited by applicant]
Choe et al. (2016) “Fc-Binding Ligands of Immunoglobulin G: An Overview of High Affinity Proteins and Peptides,” Materials 9(12): 994. 17 pages.
[cited by applicant]
Cunningham and Wells (1989) “High-resolution epitope mapping of hGH-receptor interactions by alanine-scanning mutagenesis,” Science, 244:1081-1085.
[cited by applicant]
Davies et al., “Antibody-antigen complexes,” Annual Rev Biochem. 59:439-473, (1990).
[cited by applicant]
Dennis et al. (2002), “Albumin binding as a general strategy for improving the pharmacokinetics of proteins,” JBC 277(38): 35035-35043.
[cited by applicant]
Dubowchik et al., “Doxorubicin Immunoconjugates Containing Bivalent, Lysosomally-Cleavable Dipeptide Linkages,” Bioorg. & Med. Chem. Letters 12:1529-1532 (2002).
[cited by applicant]
Duncan and Winter, “The binding site for C1q on IgG,” Nature 322: 738-40 (1988).
[cited by applicant]
Damodaran (2010) “Protein PEGylation: An overview of chemistry and process considerations,” European Pharmaceutical Review, 15(1): 18-26.
[cited by applicant]
Firan, M., et al., “The MHC class I-related receptor, FcRn, plays an essential role in the maternofetal transfer of y-globulin in humans,” Int. Immunol. 13 (2001) 993-1002.
[cited by applicant]
Fishwild, D. et al. (1996) “High-avidity human IgG kappa monoclonal antibodies from a novel strain of minilocus transgenic mice,” Nature Biotechnology 14: 845-851.
[cited by applicant]
Graham et al., “Characteristics of a human cell line transformed by DNA from human adenovirus type 5,” J. Gen Virol. 36:59 (1977). 14 pages.
[cited by applicant]
Gunasekaran et al., “Enhancing antibody Fc heterodimer formation through electrostatic steering effects: applications to bispecific molecules and monovalent IgG,” J Biol Chem. (2010) 285(25): 19637-19646.
[cited by applicant]
Guss et al., “Structure of the IgG-binding regions of streptococcal protein G.,” EMBO J. 5:1567-1575 (1986).
[cited by applicant]
Guyer et al., “Immunoglobulin Binding by Mouse Intestinal Epithelial Cell Receptors,” J. Immunol. 117:587 (1976). 7 pages.
[cited by applicant]
Ham et al., “Media and Growth Requirements,” Meth. Enz. 58:44 (1979). 50 pages.
[cited by applicant]
Hara et al., “Overproduction of Penicillin-Binding Protein 7 Suppresses Thermosensitive Growth Defect at Low Osmolarity due to an spr Mutation of
[cited by applicant]
Hinman et al., “Preparation and characterization of monoclonal antibody conjugates of the calicheamicins: a novel and potent family of antitumor antibiotics,” Cancer Res. 53:3336-3342 (1993).
[cited by applicant]
Hudson et al., (2003). “Engineered antibodies,” Nat. Med., 9:129-134.
[cited by applicant]
Idusogie et al., (2000). “Mapping of the C1q Binding Site on Rituxan, a Chimeric Antibody with a Human IgG1 Fc,” J. Immunol., 164:4178-4184.
[cited by applicant]
Imai-Nishiya et al., (2007). “Double knockdown of a1,6-fucosyltransferase (FUT8) and GDP-mannose 4,6-dehydratase (GMO) in antibody-producing cells: a new strategy for generating fully non-fucosylated therapeutic antibod…
[cited by applicant]
International Search Report and Written Opinion for PCT/US2019/053588, dated Jan. 23, 2020. 11 pages.
[cited by applicant]
International Search Report and Written Opinion for PCT/US21/72603, dated May 24, 2022. 25 pages.
[cited by applicant]
Jefferis et al., (2009). “Human immunoglobulin allotypes: Possible implications for immunogenicity,” mAbs, 1(4):332-8.
[cited by applicant]
Jeffrey et al., (2006). “Dipeptide-based highly potent doxorubicin antibody conjugates,” Bioorganic & Med. Chem. Letters, 16:358-362.
[cited by applicant]
Jones et al. (1986). “Replacing the complementarity-determining regions in a human antibody with those from a mouse,” Nature, 321:522-525.
[cited by applicant]
Kim et al., (1994). “Localization of the site of the murine IgG1 molecule that is involved in binding to the murine intestinal Fc receptor',” European Journal of Immunology, 24:2429-2434.
[cited by applicant]
King et al., (2002). “Monoclonal Antibody Conjugates of Doxorubicin Prepared with Branched Peptide Linkers: Inhibition of Aggregation by Methoxytriethyleneglycol Chains,” J. Med. Chem., 45:4336-4343.
[cited by applicant]
Klein et al. (2012), “Progress in overcoming the chain association issue in bispecific heterodimeric lgG antibodies,” MAbs, 4(6):653-663.
[cited by applicant]
Kontermann et al., (2015). “Bispecific antibodies,” Drug Discovery Today, 20(7):838-847.
[cited by applicant]
Kozbor et al., (1984). “A human hybrid myeloma for production of human monoclonal antibodies,” J. Immunol., 133:3001-5.
[cited by applicant]
Kratz et al., (2006). “Prodrugs of anthracyclines in cancer chemotherapy,” Current Med. Chem. 13:477-523.
[cited by applicant]
Krieg et al. (2010). “Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells,” PNAS, 107(26):11906-11911.
[cited by applicant]
Lehninger, in Biochemistry, second ed., pp. 73-75, Worth Publishers, New York (1975).
[cited by applicant]
Lindmark et al., (1983). “Binding of immunoglobulins to protein A and immunoglobulin levels in mammalian sera,” J. Immunol. Meth., 62:1-13.
[cited by applicant]
Lode et al., (1998). “Targeted Therapy with a Novel Enediyene Antibiotic Calicheamicin ϑ11 Effectively Suppresses Growth and Dissemination of Liver Metastases in a Syngeneic Model of Murine Neuroblastoma,” Cancer Res., …
[cited by applicant]
Lonberg, et al. (1994). “Antigen-specific human antibodies from mice comprising four distinct genetic modifications,” Nature 368:856-859.
[cited by applicant]
Mather et al., (1982). “Culture of testicular cells in hormone-supplemented serum-free medium,” Annals N.Y. Acad. Sci., 383:44-68.
[cited by applicant]
Mather, (1980). “Establishment and characterization of two distinct mouse testicular epithelial cell lines,” Biol. Reprod. 23:243-251.
[cited by applicant]
Merchant et al., (1988). “An efficient route to human bispecific IgG,” Nat. Biotechnol., 16(7):677-681.
[cited by applicant]
Milstein et al., (1983). “Hybrid hybridomas and their use in immunohistochemistry,” Nature, 305:537. 4 pages.
[cited by applicant]
Moore et al. (2011). “A novel bispecific antibody format enables simultaneous bivalent and monovalent co-engagement of distinct target antigens,” MAbs., 3(6): 546-557.
[cited by applicant]
Mori et al., (2004). “Engineering Chinese hamster ovary cells to maximize effector function of produced antibodies using FUT8 siRNA,” Biotechnol. Bioeng. 88(7):901-908.
[cited by applicant]
Morimoto et al., (1992). “Single-step purification of F(ab')2 fragments of mouse monoclonal antibodies (immunoglobulins G1) by hydrophobic interaction high performance liquid chromatography using TSKgel Phenyl-5PW,” Jou…
[cited by applicant]
Nagy et al., (2000). “Stability of cytotoxic luteinizing hormone-releasing hormone conjugate (AN-152) containing doxorubicin 14-O-hemiglutarate in mouse and human serum in vitro: Implications for the design of preclinic…
[cited by applicant]
Nilvebrant et al., (2013). “The albumin-binding domain as a scaffold for protein engineering,” Comput. Struct. Biotechol. J., 6:e201303009, 8 pages.
[cited by applicant]
Nygren et al., (1988). “Analysis and use of the serum albumin binding domains of streptococcal protein G,” J. Mol. Recogn., 1(2):69-74.
[cited by applicant]
Okazaki et al., (2004). “Fucose depletion from human IgG1 oligosaccharide enhances binding enthalpy and association rate between IgG1 and FcgammaRIIIa,” J. Mol. Biol., 336:1239-1249.
[cited by applicant]
Omasa et al., (2008). “Decrease in antithrombin III fucosylation by expressing GDP-fucose transporter siRNA in Chinese hamster ovary cells,” J. Biosci. Bioeng., 106(2):168-173.
[cited by applicant]
Podust et al., (2016). “Extension of in vivo half-life of biologically active molecules by XTEN protein polymers,” J. Controlled Release, 240:52-66.
[cited by applicant]
Proba et al., (1995). “Functional antibody single-chain fragments from the cytoplasm of
[cited by applicant]
Puskas et al., “Development of an attenuated interleukin-2 fusion protein that can be activated by tumour-expressed proteases,” Immunology (2011) 133: 206-220.
[cited by applicant]
Ramm et al., (2000). “The periplasmic
[cited by applicant]
Reyes et al., (1982). “Expression of human B-interferon cDNA under the control of a thymidine kinase promoter from herpes simplex virus,” Nature, 297:598-601.
[cited by applicant]
Riechmann et al. (1988). “Reshaping human antibodies for therapy,” Nature, 332:323-327.
[cited by applicant]
Ridgway et al., (1996). “Knobs-into-holes' engineering of antibody CH3 domains for heavy chain heterodimerization,” Protein Eng., 9(7):617-621.
[cited by applicant]
Ripka et al., (1986). “Two chinese hamster ovary glycosylation mutants affected in the conversion of GDP-man nose to GDP-fucose,” Arch. Biochem. Biophys., 249:533-545.
[cited by applicant]
Roux et al., (1998). “Comparisons of the ability of human IgG3 hinge mutants, IgM, IgE, and IgA2, to form small immune complexes: a role for flexibility and geometry,” J Immunol, 161:4083-90.
[cited by applicant]
Sali et al. (2015). “Characterization of a Novel Human-Specific STING Agonist that Elicits Antiviral Activity Against Emerging Alphaviruses,” PloS Pathog., 11(12) :e1005324, 30 pages.
[cited by applicant]
Schlapschy et al. (2013). “PASylation: a biological alternative to PEGylation for extending the plasma half-life of pharmaceutically active proteins,” Protein Eng. Des. Sel., 26(8):489-501.
[cited by applicant]
Shields et al, (2001). “High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fe gamma R,” J. Biol. Che…
[cited by applicant]
Shields et al., (2002). “Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma RIII and antibody-dependent cellular toxicity,” J. Biol. Chem., 277(30):26733-40.
[cited by applicant]
Shinkawa et al., (2003). “The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cell…
[cited by applicant]
Siebenlist et al., (1980). “
[cited by applicant]
Simmons et al., (2002). “Expression of full-length immunoglobulins in
[cited by applicant]
Sola et al. (2007), “Modulation of protein biophysical properties by chemical glycosylation: biochemical insights and biomedical implications,” Cell. Mol. Life Sci., 64(16):2133-2152.
[cited by applicant]
Sola et al., (2009), “Effects of Glycosylation on the Stability of Protein Pharmaceuticals,” J. Pharm. Sci., 98(4): 1223-1245.
[cited by applicant]
Stites et al. (eds), Basic and Clinical Immunology, 8th Edition, Appleton & Lange, Norwalk, CT, 1994, p. 71 and Chapter 6. 1 page.
[cited by applicant]
Suresh et al., (1986). “Bispecific monoclonal antibodies from hybrid hybridomas,” Methods in Enzymology, 121:210-228.
[cited by applicant]
Tomizuka et al., (2000). “Double trans-chromosomic mice: Maintenance of two individual human chromosome fragments containing Ig heavy and K loci and expression of fully human antibodies,” Proc. Natl. Acad. Sci. USA, 97:…
[cited by applicant]
Torgov et al., (2005). “Generation of an Intensely Potent Anthracycline by a Monoclonal Antibody-β-Galactosidase Conjugate,” Bioconj. Chem., 16:717-721.
[cited by applicant]
Traunecker et al., (1991). “Bispecific single chain molecules (Janusins) target cytotoxic lymphocytes on HIV infected cells,” EMBO J., 10:3655-3659.
[cited by applicant]
U.S. Appl. No. 17/279,407, filed (Int'l) Sep. 27, 2019, by Karow et al. (a copy is not submitted herewith pursuant to the waiver of 37 C.F.R. § 1.98 (a)(2)(iii) issued by the Office on Sep. 21, 2004).
[cited by applicant]
Urlaub et al., (1980). “Isolation of Chinese hamster cell mutants deficient in dihydrofolate reductase activity,” Proc. Natl. Acad. Sci. USA, 77:4216-4220.
[cited by applicant]
Verhoeyen et al., (1988). “Reshaping human antibodies: grafting an antilysozyme activity,” Science, 239:1534-1536.
[cited by applicant]
Vitetta et al., (1987). “Redesigning nature's poisons to create anti-tumor reagents,” Science, 238:1098-1104.
[cited by applicant]
Yamane-Ohnuki et al., (2004). “Establishment of FUT8 knockout Chinese hamster ovary cells: an ideal host cell line for producing completely defucosylated antibodies with enhanced antibody-dependent cellular cytotoxicity…
[cited by applicant]
Yamane-Ohnuki et al., (2009). “Production of therapeutic antibodies with controlled fucosylation,” MAbs, 1(3):230-236.
[cited by applicant]
Yang et al., (2003). “Tailoring structure+function and pharmacokinetic properties of single-chain Fv proteins by site-specific PEGylation,” Protein Eng., 16(10):761-770.
[cited by applicant]
Yaniv, (1982). “Enhancing elements for activation of eukaryotic promoters,” Nature 297:17-18 (1982).
[cited by applicant]
Yeung et al., (2009). “Engineering Human IgG1 Affinity to Human Neonatal Fc Receptor: Impact of Affinity Improvement on Pharmacokinetics in Primates,” J. Immunol., 182:7667-7671.
[cited by applicant]
Zapata et al., (1995). “Engineering linear F(ab')2 fragments for efficient production in
[cited by applicant]