IP Library › Granted Patent US 12,502,439
Granted Patent B2
US 12,502,439 · App. 18/396,187 · Granted Dec 23, 2025

Activatable antibodies that bind epidermal growth factor receptor and methods of use thereof

Inventors: Henry Bernard Lowman (El Granada, CA); Luc Roland Desnoyers (San Francisco, CA); Shouchun Liu (Burlingame, CA); James William West (Bend, OR); Jason Gary Sagert (San Mateo, CA); Olga Vasiljeva (Cupertino, CA); Elizabeth-Edna Mary Menendez (San Mateo, CA)
Assignee: CytomX Therapeutics, Inc.
A61K49/0058A61K39/3955A61K47/68031A61K47/6849C07K16/2863C07K16/2866C07K16/30G01N33/57492G01N33/58G01N33/6872A61K2039/505C07K2317/14C07K2317/24C07K2317/56C07K2317/90C07K2317/92C07K2317/94G01N2333/71
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Quick Facts
Patent No.
US 12,502,439
App. No.
18/396,187
Granted
Dec 23, 2025
Kind
B2
Abstract

The invention relates generally to activatable antibodies that include a masking moiety (MM), a cleavable moiety (CM), and an antibody (AB) that specifically binds to epidermal growth factor receptor (EGFR), and to methods of making and using these anti-EGFR activatable antibodies in a variety of therapeutic, diagnostic and prophylactic indications.

Claims (39)

1 . A nucleic acid molecule encoding an activatable antibody that in an activated state binds Epidermal Growth Factor Receptor (EGFR), wherein the activatable antibody comprises:

an antibody or an antigen binding fragment thereof (AB) that specifically binds to EGFR, wherein the AB comprises (i) a heavy chain amino acid sequence selected from the group consisting of SEQ ID NO: 26, SEQ ID NO: 30 and SEQ ID NO: 34 and a light chain amino acid sequence comprising SEQ ID NO: 68, or (ii) a heavy chain amino acid sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 6 and SEQ ID NO: 10 and a light chain amino acid sequence comprising SEQ ID NO: 68;

a masking moiety (MM) that inhibits binding of the AB of the activatable antibody in an uncleaved state to EGFR, wherein the masking moiety comprises the amino acid sequence CISPRGCPDGPYVMY (SEQ ID NO: 14); and

a cleavable moiety (CM) coupled to the AB, wherein the CM is a polypeptide that functions as a substrate for a protease, and wherein the CM comprises the amino acid sequence LSGRSDNH (SEQ ID NO: 13),

wherein the activatable antibody in the uncleaved state has a structural arrangement from N-terminus to C-terminus as follows: MM-CM-AB or AB-CM-MM.

2 . The nucleic acid molecule of claim 1 , further comprising a nucleic acid encoding a signal peptide.

3 . The nucleic acid molecule of claim 2 , wherein the nucleic acid encoding the signal peptide is operably linked to the nucleic acid encoding the activatable antibody via a nucleic acid encoding a spacer.

4 . The nucleic acid molecule of claim 3 , wherein the nucleic acid encoding the spacer encodes an amino acid sequence that comprises QGQSGQ (SEQ ID NO: 38).

5 . A vector comprising the nucleic acid molecule of claim 1 .

6 . A method of producing an activatable antibody by culturing a cell under conditions that lead to expression of the activatable antibody, wherein the cell comprises the vector of claim 5 .

7 . A method of manufacturing an activatable antibody that in an activated state binds Epidermal Growth Factor Receptor (EGFR), the method comprising:

(a) culturing a cell comprising the nucleic acid molecule of claim 1 under conditions that lead to expression of the activatable antibody, and

(b) recovering the activatable antibody.

8 . The nucleic acid molecule of claim 1 , wherein the antigen binding fragment thereof is selected from the group consisting of a Fab fragment, a F(ab′)2 fragment, a scFv, and a scAb.

9 . The nucleic acid molecule of claim 1 , wherein the activatable antibody comprises a first linking peptide (LP1) and a second linking peptide (LP2), and wherein the activatable antibody in an uncleaved state has the structural arrangement from N-terminus to C-terminus as follows: MM-LP1-CM-LP2-AB or AB-LP2-CM-LP1-MM.

10 . The nucleic acid molecule of claim 9 , wherein at least one of LP1 or LP2 comprises an amino acid sequence selected from the group consisting of (GS)n, (GGS)n, (GSGGS)n (SEQ ID NO: 15) and (GGGS)n (SEQ ID NO: 16), where n is an integer of at least one.

11 . The nucleic acid molecule of claim 9 , wherein at least one of LP1 or LP2 comprises an amino acid sequence selected from the group consisting of GGSG (SEQ ID NO: 17), GGSGG (SEQ ID NO: 18), GSGSG (SEQ ID NO: 19), GSGGG (SEQ ID NO: 20), GGGSG (SEQ ID NO: 21), GSSSG (SEQ ID NO: 22), GSSGGSGGSGGSG (SEQ ID NO: 23), GSSGT (SEQ ID NO: 24), or GSSG (SEQ ID NO: 37).

12 . The nucleic acid molecule of claim 1 , wherein the activatable antibody in an uncleaved state comprises a spacer, wherein the spacer is joined directly to the MM and has the structural arrangement from N-terminus to C-terminus of spacer-MM-CM-AB, wherein the spacer comprises the amino acid sequence QGQSGQ (SEQ ID NO: 38).

13 . The nucleic acid molecule of claim 1 , wherein the activatable antibody is conjugated to an agent.

14 . The nucleic acid molecule of claim 13 , wherein the agent is a dolastatin, an auristatin or a derivative thereof, a maytansinoid or a derivative thereof, a duocarmycin or a derivative thereof, or a calicheamicin or a derivative thereof.

15 . The nucleic acid molecule of claim 13 , wherein the agent is conjugated to the AB via a linker.

16 . The nucleic acid molecule of claim 1 , wherein the activatable antibody further comprises a detectable moiety.

17 . A nucleic acid molecule encoding an activatable antibody that in an activated state binds Epidermal Growth Factor Receptor (EGFR), wherein the activatable antibody comprises:

an antibody or an antigen binding fragment thereof (AB) that specifically binds to EGFR, wherein the AB comprises a combination of heavy and light chains selected from the group consisting of:

(a) a heavy chain comprising amino acid sequence of SEQ ID NO: 26 and a light chain comprising the amino acid sequence of SEQ ID NO: 28;

(b) a heavy chain comprising amino acid sequence of SEQ ID NO: 2 and a light chain comprising the amino acid sequence of SEQ ID NO: 4;

(c) a heavy chain comprising amino acid sequence of SEQ ID NO: 6 and a light chain comprising the amino acid sequence of SEQ ID NO: 4;

(d) a heavy chain comprising amino acid sequence of SEQ ID NO 30 and a light chain comprising the amino acid sequence of SEQ ID NO: 28;

(e) a heavy chain comprising amino acid sequence of SEQ ID NO: 10 and a light chain comprising the amino acid sequence of SEQ ID NO: 4; and

(f) a heavy chain comprising amino acid sequence of SEQ ID NO: 34 and a light chain comprising the amino acid sequence of SEQ ID NO: 28;

a masking moiety (MM) that inhibits binding of the AB of the activatable antibody in an uncleaved state to EGFR, wherein the masking moiety comprises the amino acid sequence CISPRGCPDGPYVMY (SEQ ID NO: 14); and

a cleavable moiety (CM) coupled to the AB, wherein the CM is a polypeptide that functions as a substrate for a protease, and wherein the CM comprises the amino acid sequence LSGRSDNH (SEQ ID NO: 13),

wherein the activatable antibody in the uncleaved state has a structural arrangement from N-terminus to C-terminus as follows: MM-CM-AB or AB-CM-MM.

18 . The nucleic acid molecule of claim 17 , wherein

the activatable antibody comprises a heavy chain comprising amino acid sequence of SEQ ID NO: 26 and a light chain comprising the amino acid sequence of SEQ ID NO: 28.

19 . The nucleic acid molecule of claim 17 , wherein

the activatable antibody comprises a heavy chain comprising amino acid sequence of SEQ ID NO: 30 and a light chain comprising the amino acid sequence of SEQ ID NO: 28.

20 . The nucleic acid molecule of claim 17 , wherein

the activatable antibody comprises a heavy chain comprising amino acid sequence of SEQ ID NO: 34 and a light chain comprising the amino acid sequence of SEQ ID NO: 28.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 25, 2024
From: LOWMAN, HENRY BERNARD; DESNOYERS, LUC ROLAND; LIU, SHOUCHUN; WEST, JAMES WILLIAM; SAGERT, JASON GARY; VASILJEVA, OLGA; MENENDEZ, ELIZABETH-EDNA MARY
To: CYTOMX THERAPEUTICS, INC.
Reel/Frame 066892/0533 →
Continuity (11)
Division 16892973 · Jun 4, 2020
Division 15875947 · Jan 19, 2018
Division 15381972 · Dec 16, 2016
Division 14815111 · Jul 31, 2015
Division 13872052 · Apr 26, 2013
Provisional Application 61639796 · Apr 27, 2012
Provisional Application 61662204 · Jun 20, 2012
Provisional Application 61749220 · Jan 4, 2013
Provisional Application 61749529 · Jan 7, 2013
Provisional Application 61763237 · Feb 11, 2013
Related Publication 20240398998A1 · Dec 5, 2024
References Cited (172)
US 3773919A · Boswell et al. · 1973 [cited by applicant]
US 4522811A · Eppstein et al. · 1985 [cited by applicant]
US 5030719A · Umemoto et al. · 1991 [cited by applicant]
US 5151510A · Stec et al. · 1992 [cited by applicant]
US 5525491A · Hton et al. · 1996 [cited by applicant]
US 7465790B2 · Waldmann et al. · 2008 [cited by applicant]
US 7666817B2 · Daugherty et al. · 2010 [cited by applicant]
US 8034959B2 · Ng et al. · 2011 [cited by applicant]
US 8226945B2 · Ebens, Jr. et al. · 2012 [cited by applicant]
US 8513390B2 · Stagliano et al. · 2013 [cited by applicant]
US 8518404B2 · Daugherty et al. · 2013 [cited by applicant]
US 8529898B2 · Daugherty et al. · 2013 [cited by applicant]
US 8541203B2 · Daugherty et al. · 2013 [cited by applicant]
US 8563269B2 · Stagliano et al. · 2013 [cited by applicant]
US 8809504B2 · Lauermann · 2014 [cited by applicant]
US 8895702B2 · Williams et al. · 2014 [cited by applicant]
US 9120853B2 · Lowman et al. · 2015 [cited by applicant]
US 9169321B2 · Daugherty et al. · 2015 [cited by applicant]
US 9453078B2 · Stagliano et al. · 2016 [cited by applicant]
US 9540440B2 · Lowman et al. · 2017 [cited by applicant]
US 9545442B2 · Lowman et al. · 2017 [cited by applicant]
US 9737623B2 · Desnoyers et al. · 2017 [cited by applicant]
US 9889211B2 · Lowman et al. · 2018 [cited by applicant]
US 10059762B2 · Stagliano et al. · 2018 [cited by applicant]
US 10077300B2 · Daugherty et al. · 2018 [cited by applicant]
US 10118961B2 · Stagliano et al. · 2018 [cited by applicant]
US 10533053B2 · Lowman et al. · 2020 [cited by applicant]
US 10568977B2 · Desnoyers et al. · 2020 [cited by applicant]
US 10709799B2 · Lowman et al. · 2020 [cited by applicant]
US 11890354B2 · Lowman et al. · 2024 [cited by applicant]
US 20020016481A1 · Sasaki et al. · 2002 [cited by applicant]
US 20020127564A1 · Nolan · 2002 [cited by applicant]
US 20040109855A1 · Waldmann et al. · 2004 [cited by applicant]
US 20040111757A1 · Zhang et al. · 2004 [cited by applicant]
US 20070213511A1 · Kunz et al. · 2007 [cited by applicant]
US 20080114153A1 · Steeves et al. · 2008 [cited by applicant]
US 20080175847A1 · Yan et al. · 2008 [cited by applicant]
US 20090062142A1 · Daugherty et al. · 2009 [cited by applicant]
US 20090148905A1 · Ashman et al. · 2009 [cited by applicant]
US 20090304719A1 · Daugherty et al. · 2009 [cited by applicant]
US 20100189651A1 · Stagliano et al. · 2010 [cited by applicant]
US 20100189727A1 · Rodeck et al. · 2010 [cited by applicant]
US 20110178279A1 · Williams et al. · 2011 [cited by applicant]
US 20130004481A1 · Solca et al. · 2013 [cited by applicant]
US 20130060010A1 · Williams et al. · 2013 [cited by applicant]
US 20130315906A1 · Lowman et al. · 2013 [cited by applicant]
US 20160193332A1 · Lowman et al. · 2016 [cited by applicant]
US 20170196996A1 · Lowman et al. · 2017 [cited by applicant]
US 20180333507A1 · Lowman et al. · 2018 [cited by applicant]
US 20200270350A1 · Lowman et al. · 2020 [cited by applicant]
US 20210023243A1 · Lowman et al. · 2021 [cited by applicant]
EA 201000704 · 2010 [cited by applicant]
EP 1324771 · 2011 [cited by applicant]
WO WO199411026 · 1994 [cited by applicant]
WO WO199731024 · 1997 [cited by applicant]
WO WO199811126 · 1998 [cited by applicant]
WO WO200179271 · 2001 [cited by applicant]
WO WO2001079480 · 2001 [cited by applicant]
WO WO200191798 · 2001 [cited by applicant]
WO WO2004009638 · 2004 [cited by applicant]
WO WO2007008712 · 2007 [cited by applicant]
WO WO2007105027 · 2007 [cited by applicant]
WO WO2008101177 · 2008 [cited by applicant]
WO WO2009011572 · 2009 [cited by applicant]
WO WO2009025846 · 2009 [cited by applicant]
WO WO2009068649 · 2009 [cited by applicant]
WO WO2009140242 · 2009 [cited by applicant]
WO WO2010081173 · 2010 [cited by applicant]
WO WO2010129609 · 2010 [cited by applicant]
WO WO2011109789 · 2011 [cited by applicant]
WO WO2013043071 · 2013 [cited by applicant]
WO WO2013163631 · 2013 [cited by applicant]
WO WO2014197612 · 2014 [cited by applicant]
WO WO2015013671 · 2015 [cited by applicant]
Affara et al., “Delineating protease functions during cancer development” Proteases and Cancer, 2009, 539:1-32. [cited by applicant]
Azzopardi et al.,“Cetuximab pharmacokinetics influences progression-free survival of metastatic colorectal cancer patients” Clinical Cancer Research, Oct. 2011, 17(19):6329-37. [cited by applicant]
Bagshawe, “Antibody-directed enzyme prodrug therapy (ADEPT) for cancer” Expert review of anticancer therapy, Oct. 2006, 6(10):1421-31. [cited by applicant]
Baldrick, “Pharmaceutical excipient development: the need for preclinical guidance” Regulatory toxicology and pharmacology, Oct. 2000, 32(2):210-8. [cited by applicant]
Baselga et al., “Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin” Journal of Clinical Oncology, Feb. 14, 2000, 18(4):904-914. [cited by applicant]
Benjamin et al., “Tolerance to rat monoclonal antibodies. Implications for serotherapy” The Journal of experimental medicine, Jun. 1986, 163(6):1539-52. [cited by applicant]
Bhattacharya et al., “Impact of genetic variation on three dimensional structure and function of proteins,” PLoS One, Mar. 15, 2017 12(3):e0171355. [cited by applicant]
Boulware et al., “Evolutionary optimization of peptide substrates for proteases that exhibit rapid hydrolysis kinetics” Biotechnology and bioengineering Jun. 15, 2010, 106(3):339-46. [cited by applicant]
Bowie et al., “A method to identify protein sequences that fold into a known three-dimensional structure” Science, Jul. 12, 1991, 253(5016):164-70. [cited by applicant]
Brinks et al., “Preclinical models used for immunogenicity prediction of therapeutic proteins”, Pharmaceutical research, Jul. 2013, 30(7):1719-28. [cited by applicant]
cancer.gov [online], “Cetuximab” NCI Cancer Drug Information, 2006, retrieved on Jul. 18, 2014, retrieved from URL<http://www.cancer.gov/cancertopics/druginfo/cetuximab>, 3 pages. [cited by applicant]
Cancerres.aacrjournals.org [online], Desnoyers et al., “Abstract 4570: Development of a proteolytically activatable EGFR Probody for cancer therapy”, Apr. 15, 2013, retrieved on Oct. 15, 2015, retrieved from URL http://… [cited by applicant]
Charman, “Lipids, lipophilic drugs, and oral drug delivery—some emerging concepts” Journal of pharmaceutical sciences, Aug. 2000, 89(8):967-78. [cited by applicant]
Chiller et al., “Cellular events during induction of immunologic unresponsiveness in adult mice” The Journal of Immunology, Jun. 1971, 106(6):1647-53. [cited by applicant]
Chirinos-Rojas et al., “Use of a solid-phase random peptide library to identify inhibitors of TNF-α mediated cytotoxicity in vitro” Cytokine, Apr. 1997, 9(4):226-32. [cited by applicant]
Chothia et al., “Canonical structures for the hypervariable regions of immunoglobulins” Journal of molecular biology, Aug. 20, 1987, 196(4):901-17. [cited by applicant]
Chothia et al., “Conformations of immunoglobulin hypervariable regions” Nature, Dec. 1989, 342(6252):877-83. [cited by applicant]
Chung et al., “Cetuximab-induced anaphylaxis and IgE specific for galactose-α-1, 3- galactose” New England journal of medicine, Mar. 13, 2008, 358(11):1109-17. [cited by applicant]
Cwirla et al., “Peptides on phage: a vast library of peptides for identifying ligands” Proceedings of the National Academy of Sciences, Aug. 1990, 87(16):6378-82. [cited by applicant]
Darragh et al., “Tumor detection by imaging proteolytic activity” Cancer research, Feb. 15, 2010, 70(4):1505-12. [cited by applicant]
Davies et al., “Antibody-antigen complexes” Annual review of biochemistry, Jul. 1990, 59(1):439-73. [cited by applicant]
Donaldson et al., “Design and development of masked therapeutic antibodies to limit off-target effects: application to anti-EGFR antibodies” Cancer biology & therapy, Nov. 15, 2009, 8(22):2147-52. [cited by applicant]
drugbank.Ca, [online] “Cetuximab” DrugBank Accession No. DB00002, retrieved on Dec. 16, 2016, retrieved from URL <http://www.drugbank.ca/drugs/DB00002>10 pages. [cited by applicant]
Edwards et al., “The remarkable flexibility of the human antibody repertoire; isolation of over one thousand different antibodies to a single protein, BLyS” Journal of molecular biology, Nov. 14, 2003, 334(1):103-18. [cited by applicant]
Extended European Search Report in European Appln. No. 13780884.6, dated Mar. 3, 2016, 15 pages. [cited by applicant]
Fenton et al., “Rheostat positions: A new classification of protein positions relevant to pharmacogenomics,” Medicinal Chemistry Research, Jul. 2020, 29:1133-1146. [cited by applicant]
Francisco et al., “cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity” Blood, Aug. 15, 2003, 102(4):1458-65. [cited by applicant]
Fv Structure and Diversity in Three Dimensions, 3rd ed., New York: Raven Press, Paul (ed)., 1993, pp. 292-295. [cited by applicant]
Geysen et al., “Strategies for epitope analysis using peptide synthesis” Journal of immunological methods, Sep. 24, 1987, 102(2):259-74. [cited by applicant]
Gilliland et al., “Elimination of the immunogenicity of therapeutic antibodies” The Journal of Immunology, Mar. 15, 1999, 162(6):3663-71. [cited by applicant]
Goldstein et al., “Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model” Clinical Cancer Research, Nov. 1995, 1(11):1311-8. [cited by applicant]
Gravanis et al., “The European Medicines Agency review of ofatumumab (Arzerra®) for the treatment of chronic lymphocytic leukemia in patients refractory to fludarabine and alemtuzumab: summary of the scientific assessme… [cited by applicant]
Guo et al., “Protein tolerance to random amino acid change,” PNAS USA, Jun. 22, 2004, 101(25):9205-10. [cited by applicant]
Hale, “Synthetic peptide mimotope of the CAMPATH-1 (CD52) antigen, a small glycosylphosphatidylinositol-anchored glycoprotein” Immunotechnology, Dec. 1995, 1(3-4):175-87. [cited by applicant]
Handbook of Therapeutic Antibodies, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, Dübel (ed)., vol. 1, 2007, pp. 95-102 and 119-126. [cited by applicant]
Holliger et al., “Diabodies”: small bivalent and bispecific antibody fragments Proceedings of the National Academy of Sciences, Jul. 15, 1993, 90(14):6444-8. [cited by applicant]
Huston, et al., “Protein engineering of antibody binding sites: recovery of specific activity in an anti-digoxin single-chain Fv analogue produced in [cited by applicant]
Hutchinson, “Ezzie Developing patterns” Nature Rev Cancer, 2005, 5:341. [cited by applicant]
Hynes et al., “ErbB receptors and signaling pathways in cancer” Current opinion in cell biology, Apr. 2009, 21(2):177-84. [cited by applicant]
International Preliminary Report on Patentability in International Appln. No. PCT/US2013/038540, mailed Nov. 6, 2014, 6 pages. [cited by applicant]
International Search Report and Written Opinion in International Appln. No. PCT/US2013/038540, mailed Nov. 15, 2013, 10 pages. [cited by applicant]
Invitation to Pay Additional Fees in International Appln. No. PCT/US2013/038540, mailed Sep. 11, 2013, 2 pages. [cited by applicant]
Irving, “Probodies Empower a New Generation of Antibody Immunotherapies” InCytomX Therapeutics Inc. presentation at Keystone Symposia™ on Molecular and Cellular Biology, Feb. 8, 2015 , 25 pages. [cited by applicant]
James et al., “1.9 Å structure of the therapeutic antibody CAMPATH-1H fab in complex with a synthetic peptide antigen” Journal of molecular biology, Jun. 4, 1999, 289(2):293-301. [cited by applicant]
Jansen et al., “Immunotoxins: hybrid molecules combining high specificity and potent cytotoxicity” Immunological reviews, Feb. 1982, 62(1): 185-216. [cited by applicant]
Jensen-Jarolim et al., “Peptide mimotopes displayed by phage inhibit antibody binding to bet v 1, the major birch pollen allergen, and induce specific IgG response in mice” The FASEB journal, Dec. 1998, 12(15):1635-42. [cited by applicant]
Sequences of proteins of immunological interest, 5th ed., Kabat (ed)., NIH Publication 91-3242, 1991, p. 310. [cited by applicant]
Katz, “Structural and mechanistic determinants of affinity and specificity of ligands discovered or engineered by phage display” Annual review of biophysics and biomolecular structure, Jun. 1997, 26(1):27-45. [cited by applicant]
Killen et al., “Specific killing of lymphocytes that cause experimental autoimmune myasthenia gravis by ricin toxin-acetylcholine receptor conjugates” The Journal of Immunology, Nov. 1984, 133(5):2549-53. [cited by applicant]
Krieckaert et al., “Immunogenicity of biologic therapies—we need tolerance” Nature Reviews Rheumatology, Oct. 2010, 6(10):558-9. [cited by applicant]
Krieckaert et al., “Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner” Annals of the rheumatic diseases, Nov. 2012, 71(11): 1914-5. [cited by applicant]
LaPlanche et al., “Phosphorothioate-modified oligodeoxyribonucleotides. III. NMR and UV spectroscoptc studies of the R p-R p, S p-S p, and R p-S p duplexes, [d (GGSAATTCC)] 2, derived from diastereomeric O-ethyl phospho… [cited by applicant]
Leibiger et al., “Variable domain-linked oligosaccharides of a human monoclonal IgG: structure and influence on antigen binding” Biochemical Journal, Mar. 1999, 338(2):529-38. [cited by applicant]
Leitner et al., “A mimotope defined by phage display inhibits IgE binding to the plant panallergen profiling” European journal of immunology, Sep. 1998, 28(9):2921-7. [cited by applicant]
Li et al., “Structural basis for inhibition of the epidermal growth factor receptor by cetuximab” Cancer cell, Apr. 2005, 7(4):301-11. [cited by applicant]
Lichtenstein, “Comprehensive review: antitumor necrosis factor agents in inflammatory bowel disease and factors implicated in treatment response” Therapeutic advances in gastroenterology, Jul. 2013, 6(4):269-93. [cited by applicant]
Lloyd et al., “Modelling the human immune response: performance of a 1011 human antibody repertoire against a broad panel of therapeutically relevant antigens” Protein Engineering, Design & Selection, Mar. 2009, 22(3):1… [cited by applicant]
ludger.com, [online] “Designing Biobetter Monoclonal Antibody Therapeutics by Glycoengineering,” Oct. 2, 2009, retrieved from URL <http://www.ludger.com/articles/ludger-m-00308-intpharmind-2009-biobetter-mAbs.pdf>, 5 pa… [cited by applicant]
Malmqvist, “Biospecific interaction analysis using biosensor technology” Nature, Jan. 1993, 361(6408):186-7. [cited by applicant]
Marasco et al., “Design, intracellular expression, and activity of a human anti-human immunodeficiency virus type 1 gp120 single-chain antibody” Proceedings of the National Academy of Sciences, Aug. 15, 1993, 90(16):788… [cited by applicant]
Mitchison, The dosage requirements for immunological paralysis by soluble proteins. Immunology, Oct. 1968, 15(4):509-530. [cited by applicant]
Mitra et al., “Reagents for the crosslinking of proteins by equilibrium transfer alkylation” Journal of the American Chemical Society, May 1979, 101(11):3097-110. [cited by applicant]
Mook et al., “In situ localization of gelatinolytic activity in the extracellular matrix of metastases of colon cancer in rat liver using quenched fluorogenic DQ-gelatin” Journal of Histochemistry & Cytochemistry, Jun. … [cited by applicant]
Moore et al., “Antibodies to discontinuous or conformationally sensitive epitopes on the gp120 glycoprotein of human immunodeficiency virus type 1 are highly prevalent in sera of infected humans” Journal of Virology, Fe… [cited by applicant]
Morris “Epitope mapping: B-cell epitopes” Encyclopedia of life sciences, 2007:1-3. [cited by applicant]
Murthy et al., “Legumain expression in relation to clinicopathologic and biological variables in colorectal cancer” Clinical cancer research, Mar. 2005, 11(6):2293-9. [cited by applicant]
neb.com [online], retrieved on Jan. 11, 2012, retrieved from URL<http://www.neb.com/neb/products/phd/phd.html>, 5 pages. [cited by applicant]
Nelson et al., “Development trends for human monoclonal antibody therapeutics” Nature reviews drug discovery, Oct. 2010, 9(10):767-74. [cited by applicant]
Nielsen et al., “Urokinase plasminogen activator is localized in stromal cells in ductal breast cancer” Laboratory investigation, Nov. 2001, 81(11):1485-501. [cited by applicant]
Oligonucleotides and analogues: A Practical Approach, Oxford University Press, Eckstein (ed)., 1991, pp. 87-108. [cited by applicant]
Pirker et al., “Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial” The Lancet, May 2, 2009, 373(9674):1525-31. [cited by applicant]
Powell et al., “Compendium of excipients for parenteral formulations” PDA Journal of Pharmaceutical Science and Technology, Sep. 1998, 52(5):238-311. [cited by applicant]
Ramakrishnan et al., “Comparison of the selective cytotoxic effects of immunotoxins containing ricin A chain or pokeweed antiviral protein and anti-Thy 1.1 monoclonal antibodies” Cancer research, Jan. 1984, 44(1):201-8. [cited by applicant]
Roitt's Essential Immunology, 10th ed., Immunochemical Techniques, Roitt (ed)., 2001, Chapter 6, pp. 108, 118-120. [cited by applicant]
Rudikoff et al., “Single amino acid substitution altering antigen-binding specificity” Proceedings of the National Academy of Sciences, Mar. 1982, 79(6):1979-83. [cited by applicant]
Schwarz et al., “Mechanisms and principles of N-linked protein glycosylation” Current opinion in structural biology, Oct. 2011, 21(5):576-82. [cited by applicant]
Sciencetranslationalmedicine.org [online], Desnoyers et al., “Tumor-specific activation of an EGFR-targeting probody enhances therapeutic index” Oct. 16, 2013, retrieved on Oct. 16, 2013, retrieved from URL http://www.s… [cited by applicant]
Scott et al., “Searching for peptide ligands with an epitope library” Science, Jul. 27, 1990 249(4967):386-90. [cited by applicant]
Segaert et al., “Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors” Annals of oncology, Sep. 2005, 16(9):1425-33. [cited by applicant]
Sethu et al., “Immunogenicity to biologics: mechanisms, prediction and reduction” Archivum immunologiae et therapiae experimentalis, Oct. 2012, 60(5):331-44. [cited by applicant]
Smith et al., “Phage display” Chemical reviews, Apr. 1997, 97(2):391-410. [cited by applicant]
Stec et al., “Automated solid-phase synthesis, separation, and stereochemistry of phosphorothioate analogs of oligodeoxyribonucleotides” Journal of the American Chemical Society, Oct. 1984, 106(20):6077-9. [cited by applicant]
Stein et al., “Physicochemical properties of phospborothioate oligodeoxynucleotides” Nucleic acids research, Apr. 25, 1988 16(8):3209-21. [cited by applicant]
Tabernero et al., “Pharmacogenomic and pharmacoproteomic studies of cetuximab in metastatic colorectal cancer: biomarker analysis of a phase I dose-escalation study” Journal of clinical oncology, Mar. 2010, 28(7):1181-9. [cited by applicant]
Thornton et al., “Prediction of progress at last” Nature, Nov. 1991, 354(6349):105-6. [cited by applicant]
Tokuriki et al., Stability effects of mutations and protein evolvability, Curr. Opin. Struc. Biol, Oct. 2009, 19:596-604. [cited by applicant]
Uhlmann et al., “Antisense oligonucleotides: a new therapeutic principle” Chemical Reviews, Jun. 1990, 90(4):543-84. [cited by applicant]
Vitetta et al., “Redesigning nature's poisons to create anti-tumor reagents” Science, Nov. 20, 1987, 238(4830):1098-104. [cited by applicant]
Wang, “Lyophilization and development of solid protein pharmaceuticals” International journal of pharmaceutics, Aug. 2000, 203(1-2):1-60. [cited by applicant]
Weigle, “Recent observations and concepts in immunological unresponsiveness and autoimmunity” Clinical and experimental immunology, Oct. 1971, 9(4):437. [cited by applicant]
Wolbink et al., “Dealing with immunogenicity of biologicals: assessment and clinical relevance” Current opinion in rheumatology, May 2009, 21(3):211-5. [cited by applicant]
Wright et al., “Antibody variable region glycosylation: position effects on antigen binding and carbohydrate structure” The EMBO journal, Oct. 1991, 10(10):2717-23. [cited by applicant]
Yan et al., “Antibody-based therapy for solid tumors” The Cancer Journal, May 2008, 14(3):178-83. [cited by applicant]
Yang et al., “Generation and characterization of a target-selectively activated antibody against epidermal growth factor receptor with enhanced anti-tumor potency” InMAbs, Mar. 4, 2015, 7(2):440-450. [cited by applicant]
Yu et al., “Interaction between bevacizumab and murine VEGF-A: a reassessment” Investigative ophthalmology & visual science, Feb. 2008, 49(2):522-7. [cited by applicant]
Zeitlin et al., “Enhanced potency of a fucose-free monoclonal antibody being developed as an Ebola virus immunoprotectant” Proceedings of the National Academy of Sciences, Dec. 20, 2011, 108(51):20690-4. [cited by applicant]
Zhong et al., “Recent advances in glycosylation modifications in the context of therapeutic glycoproteins” Integrative Proteomics, Feb. 2012, 24:183-96. [cited by applicant]
Zon et al., “Phosphorothioate oligonucleotides: chemistry, purification, analysis, scale-up and future directions” Anti-cancer drug design, Dec. 1991, 6(6):539-68. [cited by applicant]