IP Library › Granted Patent US 12,492,393
Granted Patent B2
US 12,492,393 · App. 17/646,554 · Granted Dec 9, 2025

Anti-CD137 antibodies and methods of use thereof

Inventors: Yanping Xiao (Brookline, MA); Nicholas Stuart Wilson (San Carlos, CA); Benjamin Maxime Morin (Somerville, MA); Mark Arthur Findeis (Belmont, MA); Cornelia Anne Mundt (Lorrach, DE); Marc van Dijk (Bosch en Duin, NL); Dhan Sidhartha Chand (Woburn, MA); David Adam Savitsky (Boxford, MA); Dennis John Underwood (Jamaica Plain, MA); Olga Ignatovich (Cambridge, GB)
Assignees: AGENUS INC.; Ludwig Institute for Cancer Research Ltd.; Memorial Sloan-Kettering Cancer Center
C12N15/09A61K39/39558A61K45/06A61K47/6883A61K51/10C07K16/28C07K16/2818C07K16/2875C07K16/2878C07K16/468C12N5/06C12N5/0635C12N5/0636C12N15/63C12N15/64C12N15/79A61K2039/572A61K2039/577C07K2317/33C07K2317/34C07K2317/72C07K2317/75
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Quick Facts
Patent No.
US 12,492,393
App. No.
17/646,554
Granted
Dec 9, 2025
Kind
B2
Abstract

The instant disclosure provides antibodies that specifically bind to CD137 (e.g., human CD137) and increases CD137 function. Also provided are pharmaceutical compositions comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies.

Claims (39)

1 . An isolated antibody that specifically binds to human CD137, the antibody comprising a VH comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence of SEQ ID NO: 7, and a VL comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence of SEQ ID NO:8, wherein the antibody is conjugated to a cytotoxic agent, cytostatic agent, toxin, radionuclide, detectable label, or a second antibody.

2 . A method of increasing IL-2 production in human PBMCs in a subject, the method comprising administering to the subject an effective amount of an antibody that specifically binds to human CD137, the antibody comprising a VH comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence of SEQ ID NO: 7, and a VL comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence of SEQ ID NO:8, or a pharmaceutical composition thereof.

3 . The method of claim 2 , wherein the antibody or pharmaceutical composition thereof is administered systemically.

4 . The method of claim 3 , wherein the antibody or pharmaceutical composition thereof is administered intravenously.

5 . The method of claim 2 , wherein the antibody or pharmaceutical composition thereof is administered subcutaneously, intratumorally, or is delivered to a tumor draining lymph node.

6 . The method of claim 2 , further comprising administering an additional therapeutic agent to the subject.

7 . The method of claim 6 , wherein the additional therapeutic agent is a chemotherapeutic agent, a checkpoint targeting agent, an inhibitor of indoleamine-2,3-dioxygenase (IDO), or a vaccine.

8 . The method of claim 7 , wherein:

(a) the checkpoint targeting agent is selected from the group consisting of an antagonist anti-PD-1 antibody, an antagonist anti-PD-L1 antibody, an antagonist anti-PD-L2 antibody, an antagonist anti-CTLA-4 antibody, an antagonist anti-TIM-3 antibody, an antagonist anti-LAG-3 antibody, an antagonist anti-VISTA antibody, an antagonist anti-CD96 antibody, an antagonist anti-CEACAM1 antibody, an antagonist anti-TIGIT antibody, an agonist anti-GITR antibody, and an agonist anti-OX40 antibody;

(b) the inhibitor of IDO is selected from the group consisting of epacadostat, F001287, indoximod, and NLG919; or

(c) the vaccine comprises a heat shock protein peptide complex (HSPPC) comprising a heat shock protein complexed with an antigenic peptide, optionally wherein the heat shock protein is hsc70 or gp96 protein and the antigenic peptide is a tumor-associated antigenic peptide.

9 . The method of claim 2 , wherein the antibody comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively.

10 . The method of claim 2 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 7, and/or the VL comprises the amino acid sequence of SEQ ID NO: 8.

11 . The method of claim 2 , wherein the antibody comprises a heavy chain constant region selected from the group consisting of human IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 , and IgA 2 .

12 . The method of claim 11 , wherein the heavy chain constant region is an IgG 1 heavy chain constant region.

13 . The method of claim 11 , wherein:

(a) the amino acid sequence of the IgG 1 constant region comprises an N297A mutation;

(b) the amino acid sequence of the IgG 1 constant region comprises S267E and L328F mutations;

(c) the amino acid sequence of the IgG 2 constant region comprises a N297A mutation; or

(d) the amino acid sequence of the IgG 4 constant region comprises an S228P mutation.

14 . The method of claim 11 , wherein the heavy chain constant region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 15-20.

15 . The method of claim 2 , wherein the antibody comprises a light chain constant region selected from the group consisting of a human kappa light chain constant region and a human lambda light chain constant region.

16 . The method of claim 15 , wherein the light chain constant region comprises the amino acid sequence of SEQ ID NO: 22.

17 . The method of claim 2 , wherein the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 9-14 and 49-54, and/or a light chain comprising the amino acid sequence of SEQ ID NO: 21.

18 . The method of claim 17 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9, and a light chain comprising the amino acid sequence of SEQ ID NO: 21.

19 . The isolated antibody of claim 1 , wherein the antibody comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively.

20 . The isolated antibody of claim 1 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 7, and/or the VL comprises the amino acid sequence of SEQ ID NO: 8.

21 . The isolated antibody of claim 1 , wherein the antibody comprises a heavy chain constant region selected from the group consisting of human IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 , and IgA 2 .

22 . The isolated antibody of claim 21 , wherein the heavy chain constant region is an IgG 1 heavy chain constant region.

23 . The isolated antibody of claim 21 , wherein:

(a) the amino acid sequence of the IgG 1 constant region comprises an N297A mutation;

(b) the amino acid sequence of the IgG 1 constant region comprises S267E and L328F mutations;

(c) the amino acid sequence of the IgG 2 constant region comprises a N297A mutation; or

(d) the amino acid sequence of the IgG 4 constant region comprises an S228P mutation.

24 . The isolated antibody of claim 21 , wherein the heavy chain constant region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 15-20.

25 . The isolated antibody of claim 1 , wherein the antibody comprises a light chain constant region selected from the group consisting of a human kappa light chain constant region and a human lambda light chain constant region.

26 . The isolated antibody of claim 25 , wherein the light chain constant region comprises the amino acid sequence of SEQ ID NO: 22.

27 . The isolated antibody of claim 1 , wherein the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 9-14 and 49-54, and/or a light chain comprising the amino acid sequence of SEQ ID NO: 21.

28 . The isolated antibody of claim 27 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9, and a light chain comprising the amino acid sequence of SEQ ID NO: 21.

Assignments (7)
CORRECTIVE ASSIGNMENT TO CORRECT THE CONVEYING PARTY DATA SECTION TO ADD INVENTOR DENNIS JOHN UNDERWOOD PREVIOUSLY RECORDED ON REEL 59600 FRAME 693. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded Aug 26, 2025
From: XIAO, YANPING; WILSON, NICHOLAS STUART; MORIN, BENJAMIN MAXIME; FINDEIS, MARK ARTHUR; CHAND, DHAN SIDHARTHA; SAVITSKY, DAVID ADAM; UNDERWOOD, DENNIS JOHN
To: AGENUS INC.
Reel/Frame 072819/0321 →
SECURITY INTEREST Recorded Mar 31, 2025
From: AGENUS, INC.
To: LIGAND PHARMACEUTICALS INCORPORATED
Reel/Frame 070680/0634 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 14, 2022
From: IGNATOVICH, OLGA
To: AGENUS UK LIMITED
Reel/Frame 059600/0724 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 14, 2022
From: AGENUS UK LIMITED
To: AGENUS INC.
Reel/Frame 059600/0757 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 14, 2022
From: AGENUS SWITZERLAND INC.
To: AGENUS INC.
Reel/Frame 059600/0779 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 14, 2022
From: MUNDT, CORNELIA ANNE; VAN DIJK, MARC
To: AGENUS SWITZERLAND INC.
Reel/Frame 059600/0749 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 14, 2022
From: XIAO, YANPING; WILSON, NICHOLAS STUART; MORIN, BENJAMIN MAXIME; FINDEIS, MARK ARTHUR; CHAND, DHAN SIDHARTHA; SAVITSKY, DAVID ADAM
To: AGENUS INC.
Reel/Frame 059600/0693 →
Continuity (3)
Division 15951950 · Apr 12, 2018
Provisional Application 62485365 · Apr 13, 2017
Related Publication 20220235349A1 · Jul 28, 2022
References Cited (139)
US 6210669B1 · Aruffo et al. · 2001 [cited by applicant]
US 7214493B2 · Kunkel et al. · 2007 [cited by applicant]
US 7659384B2 · Jure-Kunkel et al. · 2010 [cited by applicant]
US 7829088B2 · Kwon · 2010 [cited by applicant]
US 8329197B2 · Noelle et al. · 2012 [cited by applicant]
US 8475790B2 · Jure-Kunkel · 2013 [cited by applicant]
US 8772026B2 · Chen et al. · 2014 [cited by applicant]
US 8821867B2 · Ahrens et al. · 2014 [cited by applicant]
US 9132281B2 · Zeng et al. · 2015 [cited by applicant]
US 9758589B2 · Kohrt et al. · 2017 [cited by applicant]
US 10144778B2 · Eisenbach-Schwartz et al. · 2018 [cited by applicant]
US 10174122B2 · Kwon et al. · 2019 [cited by applicant]
US 10233251B2 · Gray et al. · 2019 [cited by applicant]
US 20140234320A1 · Croft et al. · 2014 [cited by applicant]
US 20150037346A1 · Lesokhin et al. · 2015 [cited by applicant]
US 20150307620A1 · Vella et al. · 2015 [cited by applicant]
US 20150374731A1 · Maio et al. · 2015 [cited by applicant]
US 20160244528A1 · Gray et al. · 2016 [cited by applicant]
US 20170174773A1 · Davis et al. · 2017 [cited by applicant]
US 20180118841A1 · Ellmark et al. · 2018 [cited by applicant]
US 20180282422A1 · Xu et al. · 2018 [cited by applicant]
US 20180344870A1 · Xiao et al. · 2018 [cited by applicant]
US 20190031765A1 · Long et al. · 2019 [cited by applicant]
US 20190169308A1 · Dahlen et al. · 2019 [cited by applicant]
US 20190194329A1 · Akamatsu et al. · 2019 [cited by applicant]
US 20190284292A1 · Wang · 2019 [cited by applicant]
US 20190338040A1 · Keyt et al. · 2019 [cited by applicant]
US 20190352414A1 · Ellmark et al. · 2019 [cited by applicant]
US 20190382491A1 · Jure-Kunkel et al. · 2019 [cited by applicant]
US 20200010557A1 · Gajewski et al. · 2020 [cited by applicant]
US 20200017594A9 · Al-Shamkhani et al. · 2020 [cited by applicant]
US 20200017595A1 · Geujen et al. · 2020 [cited by applicant]
US 20200062854A1 · Liu et al. · 2020 [cited by applicant]
EP 3192805A1 · 2017 [cited by applicant]
WO WO2000024896A2 · 2000 [cited by applicant]
WO WO2005035584A1 · 2005 [cited by applicant]
WO WO2007134384A2 · 2007 [cited by applicant]
WO WO2012145183A2 · 2012 [cited by applicant]
WO WO2014143909A1 · 2014 [cited by applicant]
WO WO2016154544A1 · 2016 [cited by applicant]
WO WO2017040790A1 · 2017 [cited by applicant]
WO WO2017055398A2 · 2017 [cited by applicant]
WO WO2017123650A2 · 2017 [cited by applicant]
WO WO2017123673A2 · 2017 [cited by applicant]
WO WO2017181034A1 · 2017 [cited by applicant]
WO WO2017193094A1 · 2017 [cited by applicant]
WO WO2017218970A1 · 2017 [cited by applicant]
WO WO2018020273A1 · 2018 [cited by applicant]
WO WO2018045110A1 · 2018 [cited by applicant]
WO WO2018115003A2 · 2018 [cited by applicant]
WO WO2018127473A1 · 2018 [cited by applicant]
WO WO2018191502 · 2018 [cited by applicant]
Agenus—Non-Confidential Overview—Oct. 2017. [cited by applicant]
Agenus—Non-Confidential Overview—Nov. 2017. [cited by applicant]
Immunomodul Abs deck-Blair Maidstone 2017 Final—Mar. 29-30, 2017. [cited by applicant]
Akhmetzyanova, I., et al., (2016) “CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4 + T Cells with Antitumor Activity” J. Immunol. 196:484-492. [cited by applicant]
Alfaro, C., et al., (2015) “Functional expression of CD137 (4-1BB) on T helper follicular cells” OncoImmunology 4(12): e1054597. [cited by applicant]
Bartkowiak, T. et al., (2015) “4-1BB Agonists: Multi-Potent Potentiators of Tumor Immunity” Front Oncol. 8(5):117. [cited by applicant]
Bartkowiak, T. et al., (2018) “Activation of 4-1BB on Liver Myeloid Cells Triggers Hepatitis via an Interleukin-27-Dependent Pathway” Clin. Cancer Res. 24(5):1138-1151. [cited by applicant]
Belcaid Z., et al., (2014) “Focal radiation therapy combined with 4-1BB activation and CTLA-4 blockade yields long-term survival and a protective antigen-specific memory response in a murine glioma model” PloS One 9(7):… [cited by applicant]
Bitra, A., et al., (2017) “Crystal structure of murine 4-1BB and its interaction with 4-1BBL support a role for galectin-9 in 4-1BB signaling” J. Biol. Chem. 293(4):1317-1329. [cited by applicant]
Bournazos, S. et al., (2015) “Fγ receptor pathways during active and passive immunization” Immunological Reviews 268:88-103. [cited by applicant]
Bulliard, Y. et al., (2013) “Activating Fcγ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies” J. Exp. Med. 210(9):1685-93. [cited by applicant]
Bulliard, Y, et al., (2014) “OX40 engagement depletes intratumoral Tregs via activating FcγRs, leading to antitumor efficacy” Immunology and Cell Biology 92:475-480. [cited by applicant]
Chaco, J.A., et al., (2013) “Co-Stimulation through 4-1BB/CD137 Improves the Expansion and Function of CD8+ Melanoma Tumor-Infiltrating Lymphocytes for Adoptive T-Cell Therapy” PLoS One 8(4):e60031. [cited by applicant]
Chan, Siaw-Lin et al., (2009) “Epitope Mapping of a Chimeric Cd137 Mab: A Necessary Step for Assessing the Biologic Relevance of Non-Human Primate Models”, Journal of Molecular Recognition, vol. 22, No. 3, pp. 242-249. [cited by applicant]
Chester, c., et al., (2018) “Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies” Blood 131(1):49-57. [cited by applicant]
Chin, S.M., et al., (2018) “Structure of the 4-1BB/4-1BBL complex and distinct binding and functional properties of utomilumab and urelumab” Nature Communication 9:4679. [cited by applicant]
Collins, a.v., et al., (2002) “The Interaction Properties of Costimulatory Molecules Revisited” Immunity, 17:201-210. [cited by applicant]
Compte, M., et al., (2018) “A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity” Nature Communications 9:4809. [cited by applicant]
Croft, M., (2009) “The role of TNF superfamily members in T-cell function and diseases” Nature Reviews 9:271-285. [cited by applicant]
Curran, M.A., et al., (2011) “Combination CTLA-4 blockage and 4-1BB activation enhances tumor rejection by increasing t-cell infiltration, proliferation, and cytokine production” PLoS One 6(4):1-11. [cited by applicant]
De Mol, N.J., et al., (2005) “Surface Plasmon Resonance Thermodynamic and Kinetic Analysis as a Strategic Tool in Drug Design. Distinct Ways for Phosphopeptides to Plug into Src- and Grb2 SH2 Domains” J. Med. Chem. 48:7… [cited by applicant]
Dharmadhikaria, B., et al., (2016) “CD137 and CD137L signals are main drivers of type 1, cell-mediated immune responses” Oncoimmunology 5(4):e1113367. [cited by applicant]
Finco, D., et al., (2014) “Cytokine release assays: Current practices and future directions” Cytokine 66:143-155. [cited by applicant]
Fisher, T.S., et al., (2012) “Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity” Cancer Immunol Immunother. 61(10):1721-33. [cited by applicant]
Gopal, A., et al., (2015) “A phase I study of PF-05082566 (anti-4-1BB) + rituximab in patients with CD20+ NHL” J. Clin. Oncol. 33 (suppl; abstr 3004). [cited by applicant]
Gruss, H., and Dower, S.K., (1995) “Tumor Necrosis Factor Ligand Superfamily: Involvement in the Pathology of Malignant Lymphomas” Blood 85:12:3378-3404. [cited by applicant]
Guo, Z., et al., (2013) “Combined TIM-3 blockade and CD137 activation affords the long-term protection in a murine model of ovarian cancer” J. Translational Med. 11(215):1-11. [cited by applicant]
Houot, R. et al., (2014) “CD137 stimulation enhances the vaccinal effect of anti-tumor antibodies” Oncolmmunology 3(7):e941740. [cited by applicant]
Ito, F., et al., (2004) “Anti-CD137 Monoclonal Antibody Administration Augments the Antitumor Efficacy of Dendritic Cell-Based Vaccines” Cander Res. 64:8411-8419. [cited by applicant]
Kim, Y.H., et al., (2008) “Combination Therapy with Cisplatin and Anti-4-1BB: Synergistic Anti-cancer Effects and Amelioration of Cisplatin-induced Nephrotoxicity” Cancer Res. 68(18):7264-7269. [cited by applicant]
Kim, Y.H., et al., (2009) “Mechanisms involved in synergistic anticancer effects of anti-4-1BB and cyclophosphamide therapy” Mol. Cancer Ther. 8(2):469-78. [cited by applicant]
Kocak, E., et al., (2006) “Combination Therapy with Anti-CTL Antigen-4 and Anti-4-1BB Antibodies Enhances Cancer Immunity and Reduces Autoimmunity” Cancer Res. 66(14):7276-7284. [cited by applicant]
Korhrt, H.E., et al., (2011) “CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies” Blood 117(8):2423-2432. [cited by applicant]
Korhrt, H.E., et al., (2014) “Targeting CD137 enhances the efficacy of cetuximab” J. Clin. Invest. 124(6):2668-2682. [cited by applicant]
Kwon, B., et al., (2002) “Immune Responses in 4-1BB (CD137)-Deficient Mice” J. Immunol. 168:5483-5490. [cited by applicant]
Kwon, B., et al., (2018) “Anti-CD137 Cancer Immunotherapy Suppresses Tumor Growth-Response” Cancer Res. 78:1572-1573. [cited by applicant]
Langstein, J. et al., (1999) “CD137 Induces Proliferation and Endomitosis in Monocytes” Blood 94(9):3161-3168. [cited by applicant]
Lee, H., et al., (2002) “4-1BB Promotes the Survival of CD8+ T Lymphocytes by Increasing Expression of Bcl-xL and Bfl-1” J. Immunol. 169:4882-4888. [cited by applicant]
Lin, G.H.Y., et al., (2013) “GITR-Dependent Regulation of 4-1BB Expression: Implications for T Cell Memory and Anti-4-1BB-Induced Pathology” J. of Immunol. 190:4627-4639. [cited by applicant]
Lin, W. et al., (2008) “Fc-Dependent Expression of CD137 on Human NK Cells: Insights Into “Antagonistic” effects of anti-CD137 monoclonal antibodies”, Blood, vol. 112, No. 3, pp. 699-707. [cited by applicant]
Lynch, D.H., et al., (2008) “The promise of 4-1BB (CD137)-mediated immunomodulation and the immunotherapy of cancer” Immunological Reviews 222:277-286. [cited by applicant]
Melero, I., et al., (1997) “Monoclonal antibodies against the 4-IBB T-cell activation molecule eradicate established tumors” Nature Medicine 3(6):682-685. [cited by applicant]
Melero, I., et al., (1998) “Amplification of tumor immunity by gene transfer of the co-stimulatory 4-1BB ligand: synergy with the CD28 co-stimulatory pathway” Eur. J. Immunol. 28:1116-1121. [cited by applicant]
Melero, I., et al., (2008) “Multi-layered action mechanisms of CD137 (4-1BB)-targeted immunotherapies” Trends in Pharmacological Sciences 29(8):383-390. [cited by applicant]
Navabi, S.S., et al., (2015) “Natural Killer Cell Functional Activity After 4-1BB Costimulation” Inflammation 38(3):1181-1190. [cited by applicant]
Nimmerjahn, F. et al. (2008) “Fcγ receptors as regulators of immune responses” Nature Reviews 8:34-47. [cited by applicant]
Nishikawa, H., et al., (2010) “Regulatory T cells in tumor immunity” Int. J. Cancer: 127:759-767. [cited by applicant]
Petersson, K., et al., (2002) “Crystal structure of a SEA variant in complex with MHC class II reveals the ability of SEA to crosslink MHC molecules” Structure 10:1619-1626. [cited by applicant]
Pollok, E.P., et al., (1994) “4-1BB T-cell antigen binds to mature B cells and macrophages, and costimulates anti-μ-primed splenic B cells” Eur. J. Immunol. 24:367-374. [cited by applicant]
Sánchez-Paulete, A.F., et al., (2015) “Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells” Cancer Discov. 6(1):71-9. [cited by applicant]
Segal N.H., et al., (2017) “Results from an Integrated Safety Analysis of Urelumab, an Agonist Anti-CD137 Monoclonal Antibody” Clin. Cancer Res. 23(8):1929-1936. [cited by applicant]
Segal N.H., et al., (2018) “Phase I Study of Single-Agent Utomilumab (PF05082566), a 4-1BB/CD137 Agonist, in Patients with Advanced Cancer” Clin Cancer Res. 24(8):1816-1823. [cited by applicant]
Seth, A., et al., (1994) “Binary and ternary complexes between T-cell receptor class II MC and superantigen in vitro” Nature 369:324-327. [cited by applicant]
Srivastava R.M., et al., (2017) “CD137 Stimulation Enhances Cetuximab-Induced Natural Killer: Dendritic Cell Priming of Antitumor T-Cell Immunity in Patients with Head and Neck Cancer” Clin. Cancer Res. 23(3):707-716. [cited by applicant]
Starck, L., et al., (2005) “Costimulation by CD137/4-1BB inhibits T cell apoptosis and induces Bcl-xL and c-FLIPshort via phosphatidylinositol 3-kinase and AKT/protein kinase B” Eur. J. Immunol. 35: 1257-1266. [cited by applicant]
Stebbings, R., et al., (2007) “Cytokine Storm” in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics J. Immunol. 179:3325-3331. [cited by applicant]
Vidal, J., et al., “In vitro cytokine release assays for predicting cytokine release syndrome: The current state-of-the-science. Report of a European Medicines Agency Workshop” Cytokine 51:213-215. [cited by applicant]
Vidarsson, G., et al., (2014) “IgG subclasses and allotypes: from structure to effector functions” Frontiers in Immunol. 5(520):1-17. [cited by applicant]
Wei H., et al., (2013) “Combinatorial PD-1 blockade and CD137 activation has therapeutic efficacy in murine cancer models and synergizes with cisplatin” PLoS One. 8(12):1-11. [cited by applicant]
Wei H., et al., (2014) “Dual targeting of CD137 co-stimulatory and PD-1 co-inhibitory molecules for ovarian cancer immunotherapy” OncoImmunology 3:e28248. [cited by applicant]
Weigelin, B., et al., (2015) “Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb” PNA 112(24):7551-7556. [cited by applicant]
Weigelin, B., et al., (2016) “Anti-CD137 monoclonal antibodies and adoptive T cell therapy: a perfect marriage?” Cancer Immunol. Immunother. 65:493-497. [cited by applicant]
Wen, T., et al., (2002) “4-1BB Ligand-Mediated Costimulation of Human T Cells Induces CD4 and CD8 T Cell Expansion, Cytokine Production, and the Development of Cytolytic Effector Function” J. of Immnol. 168:4897-4906. [cited by applicant]
Westwood J.A., et al., (2014) “Routes of delivery for CpG and anti-CD137 for the treatment of orthotopic kidney tumors in mice” PLoS One 9(5):1-10. [cited by applicant]
Wilcox, R.A., et al., (2002) “Cutting Edge: Expression of Functional CD137 Receptor by Dendritic Cells” J. Immunol. 168:4262-4267. [cited by applicant]
Williams, J.B., et al., (2017) “The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment” J. Exp. Med. 214(2):381-400. [cited by applicant]
Wilson, N.S., et al., (2011) “An Fcγ Receptor-Dependent Mechanism Drives Antibody-Mediated Target-Receptor Signaling in Cancer Cells” Cancer Cell 19:101-113. [cited by applicant]
Wolfl, M., et al., (2007) “Activation-induced expression of CD137 permits detection, isolation, and expansion of the full repertoire of CD8+ T cells responding to antigen without requiring knowledge of epitope specifici… [cited by applicant]
Won, E., et al., (2009) “The Structure of the Timer of Human 4-1BB Ligand Is Unique among Members of the Tumor Necrosis Factor Superfamily” J. of Biol. Chem. 285(12):9202-9210. [cited by applicant]
Wu, J., et al., (2003) “Natural Killer Cells and Cancer” Cancer Res. 90:127-156. [cited by applicant]
Xiao, Y., et al., (2014) “RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance” J. Exp. Med. 211(5):943-959. [cited by applicant]
Yi, L., et al., (2014) “Human and Mouse CD137 Have Predominantly Different Binding CRDs to Their Respective Ligands” PLoS One 9(1):e86337. [cited by applicant]
Yonezawa, A., et al., (2015) “Boosting Cancer Immunotherapy with Anti-CD137 Antibody Therapy” Clin. Cancer Res. 21:3113-3120. [cited by applicant]
Zhang, X., et al., (2009) “CD137 Promotes Proliferation and Survival of Human B Cells” J. Immunol. 184:787-795. [cited by applicant]
Zhang, X., et al., (2010) “CD137 Promotes Proliferation and Survival of Human B Cells” J. Immunol. 184:787-795. [cited by applicant]
Zhang, D., et al., (2016) “Fc engineering approaches to enhance the agonism and effector functions of an anti-OX40 antibody” J. Biol. Chem. 291(53):27134-27146. [cited by applicant]
Zheng, G., et al., (2004) “The 4-1BB Costimulation Augments the Proliferation of CD4+CD25+ Regulatory T Cells” J. Immunol. 173:2428-2434. [cited by applicant]
Zhu, Y., et al., (2007) “CD137 stimulation delivers an antigen-independent growth signal for T lymphocytes with memory phenotype” Blood 109:4882-4889. [cited by applicant]
International Search Report and Written Opinion for PCT International Application No. PCT/US2018/027310, mailed Oct. 15, 2018. [cited by applicant]
Yu et al., “How to select IgG subclasses in developing anti-tumor therapeutic antibodies,” J Hematol Oncol. May 5, 2020;13(1):45. [cited by applicant]
Paul, W. E. “Structure and Function of Immunoglobins” Fundamental Immunology, 3rd Edition, 1993; 292-29. [cited by applicant]
Skolnick et al., From genes to protein structure and function: novel applications of computational approaches in the genomic era Trends in Biotechnology, 2000; 18: 34-39. [cited by applicant]
Wu et al., “Humanization of a Murine Monoclonal Antibody by Simultaneous Optimization of Framework and CDR Residues” Journal of Molecular Biology, 1999; 294: 151-162. [cited by applicant]
Bendig, M. “Humanization of Rodent Monoclonal Antibodies by CDR Grafting” Methods: a Companion to Methods in Enzymology, 1995; 8: 83-93. [cited by applicant]
Casset et al., “A peptide mimetic of an anti-CD4 monoclonal antibody by rational design” Biochemical and Biophysical Research Communications, 2003; 307: 198-205. [cited by applicant]
Maccallum et al. “Antibody-antigen Interactions: Contact Analysis and Binding Site Topography” J. Mol. Biol. 1996; 262: 732-745. [cited by applicant]
Vajdos et al., “Comprehensive Functional Maps of the Antigen-binding Site of an Anti-ErbB2 Antibody Obtained with Shotgun Scanning Mutagenesis” Journal of Molecular Biology, 2002; 320: 415-428. [cited by applicant]