IP Library › Granted Patent US 12,734,215
Granted Patent B2
US 12,734,215 · App. 17/833,235 · Granted Sep 15, 2026

Biased IL2 muteins methods and compositions

Inventors: Jan Emmerich (Redwood City, CA); Steve Kauder (San Carlos, CA); Scott Alan McCauley (San Francisco, CA); Martin Oft (Palo Alto, CA)
Assignee: SYNTHEKINE, INC.
A61K38/2013A61K35/17A61K35/76A61K39/3955A61K45/06A61K47/60A61K38/00
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,734,215
App. No.
17/833,235
Granted
Sep 15, 2026
Kind
B2
Abstract

The present disclosures related to human interleukin-2 (hIL2) muteins, pharmaceutical formulations thereof, methods for preparing interleukin-2 muteins, recombinant vectors and cells comprising nucleic acids encoding IL2 muteins and methods for the treatment of human disease.

Claims (39)

1 . A method of treating a human subject suffering from cancer, the method comprising,

administering to said subject a pharmaceutical formulation comprising a polypeptide comprising SEQ ID NO:8, wherein the administering ameliorates one or more symptoms associated with the cancer.

2 . The method of claim 1 , wherein the polypeptide is PEGylated.

3 . The method of claim 2 , wherein the polypeptide is PEGylated with a poly ethylene glycol (PEG) having a molecular weight of 10,000 to 50,000 Daltons.

4 . The method of claim 1 , wherein the pharmaceutical formulation is administered subcutaneously.

5 . The method of claim 2 , wherein the pharmaceutical formulation is administered subcutaneously.

6 . The method of claim 1 , further comprising administering a supplementary agent to said subject.

7 . The method of claim 6 , wherein said supplementary agent is selected from the group consisting of a chemotherapeutic agent, an antibody, an immune checkpoint modulator, tumor infiltrating lymphocytes (TILs), a chimeric antigen receptor (CAR)-T cell, and a physical method.

8 . The method of claim 7 , wherein the supplementary agent is an immune checkpoint inhibitor.

9 . The method of claim 8 , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

10 . The method of claim 9 , wherein the immune checkpoint inhibitor is nivolumab.

11 . The method of claim 9 , wherein the immune checkpoint inhibitor is pembrolizumab.

12 . The method of claim 2 , wherein said method further comprises administering a supplementary agent to said subject.

13 . The method of claim 12 , wherein said supplementary agent is selected from the group consisting of a chemotherapeutic agent, an antibody, an immune checkpoint modulator, tumor infiltrating lymphocytes (TILs), a CAR-T cell, and a physical method.

14 . The method of claim 12 , wherein the supplementary agent is an immune checkpoint inhibitor.

15 . The method of claim 14 , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

16 . The method of claim 14 , wherein the immune checkpoint inhibitor is nivolumab.

17 . The method of claim 14 , wherein the immune checkpoint inhibitor is pembrolizumab.

18 . The method of claim 1 , wherein the cancer is a solid tumor.

19 . The method of claim 1 , wherein the cancer is an ovarian cancer, prostate cancer or lung cancer.

20 . The method of claim 1 , wherein the cancer is colon cancer.

21 . The method of claim 2 , wherein the cancer is a solid tumor.

22 . The method of claim 2 , wherein the cancer is an ovarian cancer, prostate cancer or lung cancer.

23 . The method of claim 2 , wherein the cancer is colon cancer.

24 . The method of claim 17 , wherein the cancer is a solid tumor.

25 . The method of claim 17 , wherein the cancer is an ovarian cancer, prostate cancer or lung cancer.

26 . The method of claim 17 , wherein the cancer is colon cancer.

27 . The method of claim 1 , wherein the polypeptide is administered at a dosage of 0.001 to 0.1 mg/kg of subject body weight.

28 . The method of claim 2 , wherein the polypeptide is administered at a dosage of 0.001 to 0.1 mg/kg of subject body weight.

29 . The method of claim 1 , wherein the pharmaceutical formulation is administered weekly.

30 . The method of claim 29 , further comprising administering pembrolizumab or nivolumab by IV infusion every two weeks or every three weeks.

31 . The method of claim 2 , wherein the pharmaceutical formulation is administered weekly.

32 . The method of claim 31 , further comprising administering pembrolizumab or nivolumab by IV infusion every two weeks or every three weeks.

33 . The method of claim 6 , wherein the supplementary agent is Blinatumomab.

34 . The method of claim 6 , wherein the supplementary agent is a bispecific antibody.

35 . The method of claim 12 , wherein the supplementary agent is Blinatumomab.

36 . The method of claim 12 , wherein the supplementary agent is a bispecific antibody.

37 . The method of claim 9 , wherein the immune checkpoint inhibitor is a bispecific antibody.

38 . The method of claim 15 , wherein the immune checkpoint inhibitor is a bispecific antibody.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 9, 2026
From: EMMERICH, JAN; KAUDER, STEVE; MCCAULEY, SCOTT ALAN; OFT, MARTIN
To: SYNTHEKINE, INC.
Reel/Frame 074900/0377 →
Continuity (4)
Continuation 17149405 · Jan 14, 2021
Provisional Application 63136599 · Jan 12, 2021
Provisional Application 62961141 · Jan 14, 2020
Related Publication 20230031597A1 · Feb 2, 2023
References Cited (348)
US 4401756A · Gillis · 1983 [cited by applicant]
US 4470461A · Stapp · 1984 [cited by applicant]
US 4518584A · Mark et al. · 1985 [cited by applicant]
US 4522811A · Eppstein · 1985 [cited by applicant]
US 4530787A · Shaked · 1985 [cited by applicant]
US 4569790A · Koths · 1986 [cited by applicant]
US 4572798A · Koths · 1986 [cited by applicant]
US 4588585A · Mark et al. · 1986 [cited by applicant]
US 4604377A · Fernandes · 1986 [cited by applicant]
US 4656132A · Ben-Bassat · 1987 [cited by applicant]
US 4738927A · Taniguchi et al. · 1988 [cited by applicant]
US 4748234A · Dorin · 1988 [cited by applicant]
US 4752585A · Koths et al. · 1988 [cited by applicant]
US 4766106A · Katre · 1988 [cited by applicant]
US 4849329A · Leung · 1989 [cited by applicant]
US 4863727A · Zimmerman et al. · 1989 [cited by applicant]
US 4879111A · Chong · 1989 [cited by applicant]
US 4931543A · Halenbeck · 1990 [cited by applicant]
US 4931544A · Katre et al. · 1990 [cited by applicant]
US 4938956A · Howard et al. · 1990 [cited by applicant]
US 4992271A · Hanisch · 1991 [cited by applicant]
US RE33653E · Mark et al. · 1991 [cited by applicant]
US 5037644A · Shaked · 1991 [cited by applicant]
US 5078997A · Hora · 1992 [cited by applicant]
US 5089261A · Nitecki et al. · 1992 [cited by applicant]
US 5102872A · Singh · 1992 [cited by applicant]
US 5116943A · Koths et al. · 1992 [cited by applicant]
US 5122464A · Wilson · 1992 [cited by applicant]
US 5126132A · Rosenberg · 1992 [cited by applicant]
US 5206344A · Katre et al. · 1993 [cited by applicant]
US 5359046A · Capon et al. · 1994 [cited by applicant]
US 5419899A · Koths et al. · 1995 [cited by applicant]
US 5442043A · Fukuta · 1995 [cited by applicant]
US 5445090A · Conley, Jr. · 1995 [cited by applicant]
US 5635599A · Pastan et al. · 1997 [cited by applicant]
US 5643565A · Doyle et al. · 1997 [cited by applicant]
US 5696079A · Lane et al. · 1997 [cited by applicant]
US 5696234A · Zurawski et al. · 1997 [cited by applicant]
US 5814314A · Lando et al. · 1998 [cited by applicant]
US 5830452A · Bauer et al. · 1998 [cited by applicant]
US 5874076A · Lando et al. · 1999 [cited by applicant]
US 5900461A · Harris · 1999 [cited by applicant]
US 5931462A · Harris · 1999 [cited by applicant]
US 6168785B1 · Theze et al. · 2001 [cited by applicant]
US 6348192B1 · Chan et al. · 2002 [cited by applicant]
US 6410008B1 · Strom · 2002 [cited by applicant]
US 6436386B1 · Roberts · 2002 [cited by applicant]
US 6437025B1 · Harris · 2002 [cited by applicant]
US 6448369B1 · Bentley · 2002 [cited by applicant]
US 6451308B1 · Strom · 2002 [cited by applicant]
US 6468798B1 · Debs · 2002 [cited by applicant]
US 6495659B2 · Bentley · 2002 [cited by applicant]
US 6514491B1 · Bentley · 2003 [cited by applicant]
US 6515100B2 · Harris · 2003 [cited by applicant]
US 6548055B1 · Lane et al. · 2003 [cited by applicant]
US 6596853B1 · Theze et al. · 2003 [cited by applicant]
US 6617135B1 · Gillies · 2003 [cited by applicant]
US 6689353B1 · Wang et al. · 2004 [cited by applicant]
US 6825334B1 · Theze et al. · 2004 [cited by applicant]
US 6929791B2 · Theze et al. · 2005 [cited by applicant]
US 6955807B1 · Shanafelt et al. · 2005 [cited by applicant]
US 7091321B2 · Gillies · 2006 [cited by applicant]
US 7101965B2 · Theze et al. · 2006 [cited by applicant]
US 7105653B2 · Shanafelt et al. · 2006 [cited by applicant]
US 7186804B2 · Gillies et al. · 2007 [cited by applicant]
US 7371371B2 · Epstein et al. · 2008 [cited by applicant]
US 7462350B2 · Gillies · 2008 [cited by applicant]
US 7514073B2 · Epstein et al. · 2009 [cited by applicant]
US 7569215B2 · Wittrup et al. · 2009 [cited by applicant]
US 7662368B2 · Theze · 2010 [cited by applicant]
US 7704490B2 · Theze · 2010 [cited by applicant]
US 7888071B2 · Gillies · 2011 [cited by applicant]
US 7951360B2 · Wittrup et al. · 2011 [cited by applicant]
US 8124066B2 · Epstein et al. · 2012 [cited by applicant]
US 8349311B2 · Wittrup et al. · 2013 [cited by applicant]
US 8759486B2 · León Monzón et al. · 2014 [cited by applicant]
US 8906356B2 · Wittrup et al. · 2014 [cited by applicant]
US 9206243B2 · León Monzón et al. · 2015 [cited by applicant]
US 9266938B2 · Ast et al. · 2016 [cited by applicant]
US 9428567B2 · Garcia et al. · 2016 [cited by applicant]
US 9580486B2 · Gavin · 2017 [cited by applicant]
US 9616105B2 · Paulsen et al. · 2017 [cited by applicant]
US 9669071B2 · Klatzmann et al. · 2017 [cited by applicant]
US 9732134B2 · Gavin et al. · 2017 [cited by applicant]
US 9844582B2 · Wittrup et al. · 2017 [cited by applicant]
US 9861705B2 · Bossard et al. · 2018 [cited by applicant]
US 10010587B2 · Addepalli et al. · 2018 [cited by applicant]
US 10035836B1 · Greve et al. · 2018 [cited by applicant]
US 10086046B2 · Paulsen et al. · 2018 [cited by applicant]
US 10093711B2 · Kannan · 2018 [cited by applicant]
US 10150802B2 · Garcia et al. · 2018 [cited by applicant]
US 10166257B2 · Wardell et al. · 2019 [cited by applicant]
US 10174091B1 · Higginson-Scott et al. · 2019 [cited by applicant]
US 10183980B2 · Garcia et al. · 2019 [cited by applicant]
US 10293028B2 · Klatzmann et al. · 2019 [cited by applicant]
US 10654905B2 · Garcia · 2020 [cited by applicant]
US 11491205B2 · Emmerich et al. · 2022 [cited by applicant]
US 20020041865A1 · Austin · 2002 [cited by applicant]
US 20030166163A1 · Gillies · 2003 [cited by applicant]
US 20040175357A1 · Shanafelt · 2004 [cited by applicant]
US 20060008872A1 · Chung et al. · 2006 [cited by applicant]
US 20060199250A1 · Zhao et al. · 2006 [cited by applicant]
US 20060269515A1 · Denis-Mize et al. · 2006 [cited by applicant]
US 20060292116A1 · Epstein et al. · 2006 [cited by applicant]
US 20070274948A1 · Hurst et al. · 2007 [cited by applicant]
US 20090098609A1 · Gillies et al. · 2009 [cited by applicant]
US 20100028350A1 · Jevnikar et al. · 2010 [cited by applicant]
US 20100273723A1 · Theze · 2010 [cited by applicant]
US 20100285014A1 · Cox · 2010 [cited by applicant]
US 20110091413A1 · Epstein et al. · 2011 [cited by applicant]
US 20110150826A1 · Paulsen · 2011 [cited by applicant]
US 20120315245A1 · León Monzón et al. · 2012 [cited by applicant]
US 20140046026A1 · Garcia · 2014 [cited by applicant]
US 20140328791A1 · Bossard · 2014 [cited by applicant]
US 20140343252A1 · Gavin · 2014 [cited by applicant]
US 20150017120A1 · Wittrup et al. · 2015 [cited by applicant]
US 20150218260A1 · Klein et al. · 2015 [cited by applicant]
US 20160208017A1 · Ast et al. · 2016 [cited by applicant]
US 20170015722A1 · Garcia · 2017 [cited by applicant]
US 20170044229A1 · Garcia et al. · 2017 [cited by applicant]
US 20170137485A1 · Gavin et al. · 2017 [cited by applicant]
US 20170304402A1 · Klatzmann et al. · 2017 [cited by applicant]
US 20170313753A1 · Gavin et al. · 2017 [cited by applicant]
US 20180016316A1 · Garcia et al. · 2018 [cited by applicant]
US 20180125941A1 · Greve et al. · 2018 [cited by applicant]
US 20180142037A1 · Ast et al. · 2018 [cited by applicant]
US 20180228842A1 · Garcia et al. · 2018 [cited by applicant]
US 20180237489A1 · Kannan · 2018 [cited by applicant]
US 20180303754A1 · Mariau · 2018 [cited by applicant]
US 20180319859A1 · Gavin et al. · 2018 [cited by applicant]
US 20180326010A1 · Deak et al. · 2018 [cited by applicant]
US 20180340014A1 · Viney et al. · 2018 [cited by applicant]
US 20190022239A1 · Hamzah et al. · 2019 [cited by applicant]
US 20190023760A1 · Bode · 2019 [cited by applicant]
US 20190060407A1 · Klatzmann et al. · 2019 [cited by applicant]
US 20190062395A1 · Merchant et al. · 2019 [cited by applicant]
US 20190106488A1 · Rondon · 2019 [cited by applicant]
US 20190119346A1 · Garcia et al. · 2019 [cited by applicant]
US 20190202917A1 · Campbell · 2019 [cited by applicant]
US 20190263877A1 · Yeung · 2019 [cited by applicant]
US 20200299349A1 · Garcia · 2020 [cited by applicant]
EP 338841A1 · 1989 [cited by applicant]
EP 2279753B1 · 2015 [cited by applicant]
EP 2918285B1 · 2015 [cited by applicant]
EP 3102595B1 · 2018 [cited by applicant]
JP 2005507870A · 2005 [cited by applicant]
JP 2017518361A · 2017 [cited by applicant]
WO 9947178A1 · 1999 [cited by applicant]
WO 1999060128A1 · 1999 [cited by applicant]
WO 2005086751A2 · 2005 [cited by applicant]
WO 2008156712A1 · 2008 [cited by applicant]
WO 2012088446A1 · 2012 [cited by applicant]
WO 2012119093A1 · 2012 [cited by applicant]
WO 2013177187A2 · 2013 [cited by applicant]
WO 2014153111A2 · 2014 [cited by applicant]
WO 2014201378A1 · 2014 [cited by applicant]
WO 2015164815A1 · 2015 [cited by applicant]
WO 2016014428A1 · 2016 [cited by applicant]
WO 2016014428A2 · 2016 [cited by applicant]
WO 2016025385A1 · 2016 [cited by applicant]
WO 2017068031A1 · 2017 [cited by applicant]
WO 2017093410A1 · 2017 [cited by applicant]
WO 2017220989A1 · 2017 [cited by applicant]
WO 2018119114A1 · 2018 [cited by applicant]
WO 2018234862A1 · 2018 [cited by applicant]
WO 2019028419A1 · 2019 [cited by applicant]
WO 2019104092A1 · 2019 [cited by applicant]
WO 2019177986A1 · 2019 [cited by applicant]
WO 2019222295A1 · 2019 [cited by applicant]
WO 2019246404A1 · 2019 [cited by applicant]
WO 2020069398A1 · 2020 [cited by applicant]
WO 2021146485A2 · 2020 [cited by applicant]
WO 2021146481A1 · 2021 [cited by applicant]
WO 2021146485A1 · 2021 [cited by applicant]
Yaghoubi et al (Biomedicine & Pharmacotherapy, 2019, vol. 110, pp. 312-318) (Year: 2019). [cited by examiner]
Schneider et al (Journal of Thoracic Oncology, 2011, vol. 6, pp. 432-438) (Year: 2011). [cited by examiner]
Abstract of Eikawa et al (Cancer Research, 2010, vol. 70, No. 8., suppl., abstract No. 1915) (Year: 2010). [cited by examiner]
Rozkova et al (Clinical Immunology, 2009, vol. 131, pp. 1-10) (Year: 2009). [cited by examiner]
Koopmans et al (Oncoimmunology, 2018, vol. 7, e1466016, 11 pages). (Year: 2018). [cited by examiner]
Au et al (The Oncologist, ePub Nov. 14, 2019, vol. 25, e709-e715) (Year: 2019). [cited by examiner]
Baluna et al., “Evidence for a Structural Motif in Toxins and Interleukin-2 That May Be Responsible for Binding to Endothelial Cells and Initiating Vascular Leak Syndrome”, Proceedings of the National Academy of Science… [cited by applicant]
Conlon et al., “Cytokines in the Treatment of Cancer”, Journal of Interferon & Cytokine Research, vol. 39, No. 1, Jan. 2019, pp. 1-16. [cited by applicant]
Meghnem et al., “Cutting Edge: Differential Fine-Tuning of IL-2-and IL-15-Dependent Functions by Targeting Their Common IL-2/15Rβ/γc Receptor”, The Journal of Immunology, vol. 198, No. 12, Jun. 2017, pp. 4563-4568. [cited by applicant]
Mizui , “Natural and Modified IL-2 for the Treatment of Cancer and Autoimmune Diseases”, Clinical Immunology, vol. 206, Sep. 2019, pp. 63-70. [cited by applicant]
Perez Horta et al., “Human and Murine IL2 Receptors Differentially Respond to the Human-IL2 Component of Immunocytokines”, OncoImmunology, vol. 8, No. 6, e1238538, 2019, 15 pages. [cited by applicant]
Pol et al., “Effects of Interleukin-2 in Immunostimulation and Immunosuppression”, Journal of Experimental Medicine, vol. 217, No. 1, 2020, pp. 1-15. [cited by applicant]
Bazan, et al (1992) Unraveling the Structure of IL-2 Science 257:410-413. [cited by applicant]
Berndt, et al (1994) Biochemistry 33:6571-76. [cited by applicant]
Imler et al. Identification of three adjacent amino acids of interleukin-2 receptor beta chain which control the affinity and the specificity of the interaction with interleukin-2. The EMBO journal. Jun. 1992;11(6):2047… [cited by applicant]
Jones, E. (2019) Designer protein delivers signal of choice; Nature 565:165-166. [cited by applicant]
Kagoya et al. A novel chimeric antigen receptor containing a JAK-STAT signaling domain mediates superior antitumor effects. Nature medicine. Mar. 2018;24(3):352. [cited by applicant]
Kallal et al. Changing partners at the dance: variations in STAT concentrations for shaping cytokine function and immune responses to viral infections. Jak-Stat. Jan. 1, 2013;2(1):e23504. [cited by applicant]
Klingmüller et al. Multiple tyrosine residues in the cytosolic domain of the erythropoietin receptor promote activation of STAT5. Proceedings of the National Academy of Sciences. Aug. 6, 1996;93(16):8324-8. [cited by applicant]
Leon, et al (2013) Mathematical models of the impact of IL2 modulation therapies on T cell dynamics Frontiers in [cited by applicant]
Leon, et al Combining computational and experimental biology to develop therapeutically valuable IL2 muteins (2018) [cited by applicant]
Levin, et al (2012) Exploiting a natural conformational switch to engineer an Interleukin-2 superkine; [cited by applicant]
Mackall. Engineering a designer immunotherapy. Science. Mar. 2, 2018;359(6379):990-1. [cited by applicant]
Malek et al., (2010) Interleukin-2 Receptor Signaling: At the Interface between Tolerance and Immunity Immunity 33:153-165. [cited by applicant]
Mitra et al. Interleukin-2 activity can be fine tuned with engineered receptor signaling clamps. Immunity. May 19, 2015;42(5):826-38. [cited by applicant]
Naeger et al. Identification of a STAT4 binding site in the interleukin-12 receptor required for signaling. Journal of Biological Chemistry. Jan. 22, 1999;274(4):1875-8. [cited by applicant]
Peterson, et al (2018) A long-lived IL-2 mutein that selectively activates and expands regulatory T cells as a therapy for autoimmune disease; Journal of Autoimmunity 95:1-14. [cited by applicant]
Rao, et al (2005) Biochemistry 44:10696-10701. [cited by applicant]
Rao, et al (2004) Molecular Pharmacology 66:864-869. [cited by applicant]
Rao, et al (2003) Protein Engineering 16(12):1081-1087. [cited by applicant]
Ring, et al (2012) Mechanistic and structural insight into the functional dichotomy between interleukin-2 and interleukin-15; [cited by applicant]
Rojas, et al. (2018) Directed evolution of super-secreted variants from phage-displayed human Interleukin-2; Scientific Reports 9:800; | DOI:10.1038/s41598-018-37280-5. [cited by applicant]
Rozwarski, et al (1994) Structural Comparisons Among the Short Chain Helical Cytokines; Strucutre 2(3); 159-173. [cited by applicant]
Schmitz et al. The cytoplasmic tyrosine motifs in full-length glycoprotein 130 have different roles in IL-6 signal transduction. The Journal of Immunology. Jan. 15, 2000;164(2):848-54. [cited by applicant]
Sim, et al (2016) IL2 Variant Circumvents ICOSb Regulatory T-cell Expansion and Promotes NK Cell Activation; Cancer Immunol Res; 4(11):983-994. [cited by applicant]
Smith (1993) Lowest Dose Interleukin-2 Immunotherapy [cited by applicant]
Sockolosky et al. Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes. Science. Mar. 2, 2018;359(6379):1037-42. [cited by applicant]
Waldmann the multi-subunit interleukin-2 receptor. Annual review of biochemistry. Jul. 1989;58(1):875-905. [cited by applicant]
Wang, et al (1997) 126Gln is the residue of human IL-2 binding to IL-2R γ subunit*; Science in China Series C: Life Sciences 40(2):159-168. [cited by applicant]
Wang, et al (2005) Science 310:1159-1163. [cited by applicant]
Ward et al. IL-2/CD25: a long-acting fusion protein that promotes immune tolerance by selectively targeting the IL-2 receptor on regulatory T cells. The Journal of Immunology. Nov. 1, 2018;201(9):2579-92. [cited by applicant]
Yang et al., (2000) Molecular modeling on some human interleukins sharing γc of interleukin-2 receptor, and structure-function relationships Journal of Molecular Structure: Theochem; 532:1-10. [cited by applicant]
Zurawski, et al. (1988) EMBO J. 7(4):1061-1069. [cited by applicant]
Zurawski, et al. (1990) EMBO J. 9(12):3899-3905. [cited by applicant]
Zurawski, et al. (1993) EMBO J. 12(13):5113-5119. [cited by applicant]
Rosalia, et al 2014) Use of enhanced interleukin-2 formulations for improved immunotherapy against cancer DOI: https://doi.org/10.1016/j.cbpa.2014.09.006. [cited by applicant]
Ju, et al (1987) Structure-Function Analysisof Human Interleukin-2 Journal of Biological Chemistry 262(12)5723-5731. [cited by applicant]
Tsytsikov, et al (1996) Identification and Characterization of Two Alternative Splice Variants of Human Interleukin-2; Journal of Biological Chemistry 271(38):23055-23060. [cited by applicant]
Fiers, et al (1983) Molecular cloning of human interieukin 2 cDNA and its expression in [cited by applicant]
Silva, et al (2019De novo design of potent and selective mimics of IL-2 and IL-15 Nature 565:186-191. [cited by applicant]
Liu, et al (2009) Engineered Interleukin-2 Antagonists for the Inhibition of Regulatory T cells [cited by applicant]
Bukowski, R. (1997) Natural History and Therapy of Metastatic Renal Cell Carcinoma—The Role of Interleukin-2; Cancer 80(7):1198-1220. [cited by applicant]
Vlasveld et al., (1994) Recombinant interleukin-2 in cancer: basic and clinical aspects ; Cancer Treatment Review 20(3):275-311. [cited by applicant]
Smith, K. (2006) The structure of IL2 bound to the three chains of the IL2 receptor and how signaling occurs; [cited by applicant]
Carmenate, et al (2013) Human IL-2 Mutein with Higher Antitumor Efficacy Than Wild Type IL-2 [cited by applicant]
Collins, et al (1988) Identification of specific residues of human interleukin 2 that affect binding to the 70-kDa subunit (p70) of the interleukin 2 receptor Proc. Nati. Acad. Sci. USA 85:7709-7713. [cited by applicant]
Kim, et al (2001) The Basis for IL-2-Induced IL-2 Receptor □ Chain Gene Regulation: Importance of Two Widely Separated IL-2 Response Elements Immunity 15:159-17. [cited by applicant]
Stauber, et al (2006) Crystal structure of the IL-2 signaling complex: Paradigm for a heterotrimeric cytokine receptor PNAS 103(8): 2788-2793. [cited by applicant]
Kreig, 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]
Meyers, et al (1991) A phase I study including pharmacokinetics of polyethylene glycol conjugated interleukin-2; Clinical Pharmacology & Therapeutics 49(3):307-13. [cited by applicant]
Katre, et al (1990) Immunogenicity of recombinant IL-2 modified by covalent attachment of polyethylene glycol; The Journal of Immunology 144(1):209-13. [cited by applicant]
Jevsevar, et al (2010) PEGylation of therapeutic proteins; Biotechnol. J. 5: 113-128. [cited by applicant]
Goodson, et al., (1990). Site-Directed Pegylation of Recombinant Interleukin-2 at its Glycosylation Site; Biotechnology 8:343-346. [cited by applicant]
Wang, et al (1995) Two Partial Antagonists of Human Interleukin2; Chinese Science Abstracts Series B > 1995 > 14 > 6 Part B > 4748. [cited by applicant]
Gillies, et al. (2011) A Low-Toxicity IL-2-Based Immunocytokine Retains Antitumor Activity Despite Its High Degree of IL-2 Receptor Selectivity; Clinical Cancer Research 17(11): 3673-3685. [cited by applicant]
Office Action in U.S. Appl. No. 17/320,174, mailed Sep. 30, 2021, 32 pages. [cited by applicant]
International Preliminary Report on Patentability issued in Internationa Application No. PCT/US2014/042341, dated Dec. 15, 2015, 10 pages. [cited by applicant]
Argos P. A possible homology between immunodeficiency virus p24 core protein and picornaviral VP2 coat protein: prediction of HIV p24 antigenic sites. The EMBO journal. Mar. 1989;8(3):779-85. [cited by applicant]
Altschul, et al. Basic local alignment search tool. Journal of molecular biology. Oct. 5, 1990;215(3):403-10. [cited by applicant]
Baldari et al. A novel leader peptide which allows efficient secretion of a fragment of human interleukin 1 beta in [cited by applicant]
Baldassari et al. Daclizumab: development, clinical trials, and practical aspects of use in multiple sclerosis. Neurotherapeutics. Oct. 2017;14(4):842-58. [cited by applicant]
Bergmann CA. The amphipathicity of interleukin-2 (Doctoral dissertation, Case Western Reserve University (Health Sciences)). [cited by applicant]
Bielekova et al. Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon β. Proceedings of the National Academy of Sciences. Jun. 8, 2004;101(23):8705-8. [cited by applicant]
Blanar et al. Interaction cloning: identification of a helix-loop-helix zipper protein that interacts with c-Fos. Science. May 15, 1992;256(5059):1014-8. [cited by applicant]
Boder et al. Yeast surface display for screening combinatorial polypeptide libraries. Nature biotechnology. Jun. 1997;15(6):553-7. [cited by applicant]
Boozarpour et al. Bacterial overexpression of the human interleukin-2 in insoluble form via the pET Trx fusion system. Iranian Journal of Biotechnology. Oct. 1, 2010;8(4):270-4. [cited by applicant]
Busse et al, Daclizumab Asthma Study Group. Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a randomized, controlled trial. American journal of respiratory and critical care med… [cited by applicant]
Buter J. Clinical studies with biological response modifiers in the treatment of solid tumors. [University Library Groningen][Host]; 1994. [cited by applicant]
Carneiro et al. When three is not a crowd: a crossregulation model of the dynamics and repertoire selection of regulatory CD4+ T cells. Immunological reviews. Apr. 2007:216(1):48-68. [cited by applicant]
Cassell et al. Therapeutic enhancement of IL-2 through molecular design. Current pharmaceutical design. Nov. 1, 2002;8(24):2171-83. [cited by applicant]
Cate et al. Isolation of the bovine and human genes for Müllerian inhibiting substance and expression of the human gene in animal cells. Cell. Jun. 6, 1986;45(5):685-98. [cited by applicant]
Chang et al. Structural analogs of interleukin-2: a point mutation that facilitates biological response. Molecular pharmacology. Jan. 1, 1995;47(1):206-11. [cited by applicant]
Chang-Cheng, “Searching for Peptide Ligands of Interleukin-2 Receptor a Chain in Phage-Displayed Peptide Library,” Chemical Research in Chinese Universities, 14(4):430-432. [cited by applicant]
Charych et al. NKTR-214, an engineered cytokine with biased IL2 receptor binding, increased tumor exposure, and marked efficacy in mouse tumor models. Clinical Cancer Research. Feb. 1, 2016;22(3):680-90. [cited by applicant]
Chen et al. A novel human IL-2 mutein with minimal systemic toxicity exerts greater antitumor efficacy than wild-type IL-2. Cell death & disease. Sep. 24, 2018;9(10):1-2. [cited by applicant]
Database Genbank (Jul. 28, 2020) “Cytokine Receptor Subunit Gamma Isoform a Precursor [Mus Musculus]” Genbank Accession No. NP_038591.1, 3 pages. [cited by applicant]
Database Genbank (Jul. 25, 2020) “Cytokine Receptor Common Subunit Gamma Precursor [ [cited by applicant]
Database Genbank (Jul. 24, 2020) “ [cited by applicant]
Database Genbank (Jul. 23, 2020) “ [cited by applicant]
Database Genbank (Jul. 25, 2020) “ [cited by applicant]
Database Genbank (Jul. 11, 2020) “Interleukin-2 Precursor [ [cited by applicant]
Database Genbank (Jul. 24, 2020) “Interleukin-2 Receptor Subunit Alpha Isoform 1 Precursor [ [cited by applicant]
Database Genbank (Jul. 23, 2020) “Interleukin-2 Receptor Subunit Beta Precursor Precursor [ [cited by applicant]
Database Genbank (Jul. 28, 2020) “Mus Musculus Interleukin 2 Receptor, Gamma Chain (II2rg), Transcript Variant A, Mrna” Genbank Accession No. NP_013563.4, 4 pages. [cited by applicant]
Devereux et al. A comprehensive set of sequence analysis programs for the VAX. Nucleic acids research. Jan. 11, 1984;12(1Part1):387-95. [cited by applicant]
Dhupkar, Pooja. “Targeting PD-1/PDL-1 Signaling in the Treatment of Osteosarcoma Lung Metastasis.” (Dec. 2016), UT GSBS Dissertations and Theses,208 pages. [cited by applicant]
Diab et al. Bempegaldesleukin (NKTR-214) plus nivolumab in patients with advanced solid tumors: phase I dose-escalation study of safety, efficacy, and immune activation (PIVOT-02). Cancer discovery. Aug. 1, 2020;10(8):1… [cited by applicant]
Drescher et al. Surface plasmon resonance (SPR) analysis of binding interactions of proteins in inner-ear sensory epithelia. InAuditory and Vestibular Research 2009 (pp. 323-343). Humana Press. [cited by applicant]
Epstein et al. Identification of a protein fragment of interleukin 2 responsible for vasopermeability. Journal of the National Cancer Institute. May 21, 2003;95(10):741-9. [cited by applicant]
Frick et al. Interleukin-2 functionalized nanocapsules for T cell-based immunotherapy. Acs Nano. Oct. 25, 2016;10(10):9216-26. [cited by applicant]
Fujita et al. Structure of the human interleukin 2 gene. Proceedings of the National Academy of Sciences. Dec. 1, 1983;80(24):7437-41. [cited by applicant]
Fukushima et al., “Carbohydrate recognition mechanism of interleukin 2 and its physiological significance,” The Journal of Biological Chemistry, 276(33):31202-31208. [cited by applicant]
Fukushima et al. Carbohydrate recognition site of interleukin-2 in relation to cell proliferation. Journal of Biological Chemistry. Aug. 1, 2001;276(33):31202-8. [cited by applicant]
Gai S. Engineering persistent interleukin-2 for cancer immunotherapy (Doctoral dissertation, Massachusetts Institute of Technology), 2012, 113 pages. [cited by applicant]
Garber K. Cytokine resurrection: engineered IL-2 ramps up immuno-oncology responses. Nature biotechnology. May 1, 2018;36(5):378-80. [cited by applicant]
Hollander, “On the stochastic regulation of interleukin-2 transcription,” Seminars in Immunology, 11(5), 2 pages. [cited by applicant]
Gold et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (Select): a randomised, double-blind, placebo-controlled trial. The Lancet. Jun. 22, 2013;381(9884):2167-75. [cited by applicant]
Hershberger et al. Daclizumab to prevent rejection after cardiac transplantation. New England Journal of Medicine. Jun. 30, 2005;352(26):2705-13. [cited by applicant]
Jacques et al. “The renewal of interleukin 2,” Medical Sciences Paris, 32(6-7):612-618, 9 pages. [cited by applicant]
Jiang et al. Interleukin-2: structural and biological relatedness to opioid peptides. Neuroimmunomodulation. 2000;8(1):20-4. [cited by applicant]
Kaartinen et al. Low interleukin-2 concentration favors generation of early memory T cells over effector phenotypes during chimeric antigen receptor T-cell expansion. Cytotherapy. Jun. 1, 2017;19(6):689-702. [cited by applicant]
Kalsoom, “Computer-Guided Design and Synthesis of IL-2 Inhibitors as Immunomodulating Agents,” Departmentr of Chemistry, 181 pages. [cited by applicant]
Kaufman et al. Construction of a modular dihydrofolate reductase cDNA gene: analysis of signals utilized for efficient expression. Molecular and cellular biology. Nov. 1982;2(11):1304-19. [cited by applicant]
Kaufman et al. Translational efficiency of polycistronic mRNAs and their utilization to express heterologous genes in mammalian cells. The EMBO journal. Jan. 1987;6(1):187-93. [cited by applicant]
Krinks et al. KY1043, a novel PD-L1 IL-2 immunocytokine directed towards CD25, delivers potent anti-tumour activity in vitro and in vivo, Kymab P625, 1 page. [cited by applicant]
Kurjan et al. Structure of a yeast pheromone gene (MFα): a putative α-factor precursor contains four tandem copies of mature α-factor. Cell. Oct. 1, 1982;30(3):933-43. [cited by applicant]
Langowski et al. Abstract, Cancer Immunology Research, 2016, vol. 4, No. 11, Abstract No. B057, 2016. [cited by applicant]
Langowski et al. NKTR-358: a selective, first-in-class IL-2 pathway agonist which increases number and suppressive function of regulatory T cells for the treatment of immune inflammatory disorders. Arthritis Rheumatol. … [cited by applicant]
Leclair et al. The p50 subunit of NF-kappa B associates with the NF-IL6 transcription factor. Proceedings of the National Academy of Sciences. Sep. 1, 1992;89(17):8145-9. [cited by applicant]
Lee et al. Proliferin secreted by cultured cells binds to mannose 6-phosphate receptors. Journal of Biological Chemistry. Mar. 5, 1988;263(7):3521-7. [cited by applicant]
Liang et al., Characterization of human interleukin 2 derived from [cited by applicant]
Lipiäinen et al. Formulation and stability of cytokine therapeutics. Journal of pharmaceutical sciences. Feb. 1, 2015;104(2):307-26. [cited by applicant]
Liu et al. Dual targeting of innate and adaptive checkpoints on tumor cells limits immune evasion. Cell reports. Aug. 21, 2018;24(8):2101-11. [cited by applicant]
Liu et al., “Engineered Interleukin-2 Antagonists for the Inhibition of Regulatory T Cells,” Journal of Immunotherapy, 32(9):887-894. [cited by applicant]
Luckow et al. High level expression of nonfused foreign genes with Autographa californica nuclear polyhedrosis virus expression vectors. Virology. May 1, 1989;170(1):31-9. [cited by applicant]
Mao et al. Study of the molecular mechanism of interleukin-2 mutein D10 binding to IL-2 receptors by molecular simulations. Molecular Simulation. Aug. 13, 2018;44(12):973-80. [cited by applicant]
Marston F. The purification of eukaryotic polypeptides synthesized in [cited by applicant]
Mccaffrey et al. RNA interference in adult mice. Nature. Jul. 2002;418(6893):38-9. [cited by applicant]
Morris et al. Preclinical and phase I clinical trial of blockade of IL-15 using Mikβ1 monoclonal antibody in T cell large granular lymphocyte leukemia. Proceedings of the National Academy of Sciences. Jan. 10, 2006;103(… [cited by applicant]
Naing et al, editors. Immunotherapy. Springer International Publishing; Mar. 20, 2017, 183 pages. [cited by applicant]
Parisi et al. Persistence of adoptively transferred T cells with a kinetically engineered IL-2 receptor agonist. Nature communications. Jan. 31, 2020;11(1):1-2. [cited by applicant]
Pérol et al. New molecular and cellular mechanisms of tolerance: tolerogenic actions of IL-2. Suppression and Regulation of Immune Responses. 2016:11-28. [cited by applicant]
Plieth et al., “Cytokines emerge as 2018's immuno-oncology stars,” Evaluate, 1-7, Mar. 2018. [cited by applicant]
Putnam. Antisense strategies and therapeutic applications. American Journal of Health System Pharmacy. Jan. 15, 1996;53(2):151-60. [cited by applicant]
Rao BM. Interleukin-2 Engineering for improved therapeutic effectiveness (Doctoral dissertation, Massachusetts Institute of Technology). [cited by applicant]
Rao, et al. “Interleukin-2 mutants with enhanced α-receptor subunit binding affinity.” Protein engineering 16, No. 12 (2003): 1081-1087. [cited by applicant]
Ren et al. Structural and functional characterisation of ferret interleukin-2. Developmental & Comparative Immunology. Feb. 1, 2016;55:32-8. [cited by applicant]
Rodríguez-Silva et al. Scale-up purification of a mutant of recombinant human Interleukin 2 by reverse-phase high performance liquid chromatography. Biotecnología Aplicada. 2001;18(3):159-62. [cited by applicant]
Rosenberg et al. Vectors for selective expression of cloned DNAs by T7 RNA polymerase. Gene. Jan. 1, 1987;56(1):125-35. [cited by applicant]
Sambrook et al. Molecular cloning: a laboratory manual. Cold spring harbor laboratory press; 4 [cited by applicant]
Scheller et al. Immunoreceptor engineering and synthetic cytokine signaling for therapeutics. Trends in immunology. Mar. 1, 2019;40(3):258-72. [cited by applicant]
Schultz et al. Expression and secretion in yeast of a 400-kDa envelope glycoprotein derived from Epstein-Barr virus. Gene. Jan. 1, 1987;54(1):113-23. [cited by applicant]
Seed B. An LFA-3 cDNA encodes a phospholipid-linked membrane protein homologous to its receptor CD2. Nature. Oct. 1987;329(6142):840-2. [cited by applicant]
Smith et al. Production of human beta interferon in insect cells infected with a baculovirus expression vector. Molecular and cellular biology. Dec. 1983;3(12):2156-65. [cited by applicant]
Spangler, et al., 2015. Antibodies to interleukin-2 elicit selective T cell subset potentiation through distinct conformational mechanisms. Immunity, 42(5), pp. 815-825. [cited by applicant]
Spangler, et al., 2018. Engineering a single-agent cytokine/antibody fusion that selectively expands regulatory T cells for autoimmune disease therapy. The Journal of Immunology, 201(7), pp. 2094-2106. [cited by applicant]
Tchao, et al. “Amg 592 is an investigational IL-2 mutein that induces highly selective expansion of regulatory T cells.” (2017): 696-696. [cited by applicant]
Thanos, et al. “Potent small-molecule binding to a dynamic hot spot on IL-2.” Journal of the American Chemical Society 125, No. 50 (2003): 15280-15281. [cited by applicant]
Tilley, et al. “Identification of a small molecule inhibitor of the IL-2/IL-2Rα receptor interaction which binds to IL-2.” Journal of the American Chemical Society 119, No. 32 (1997): 7589-7590. [cited by applicant]
Tkaczuk, et al. “Effect of Anti-IL-2Rα Antibody on IL-2-induced Jak/STAT Signaling.” American Journal of Transplantation 2, No. 1 (2002): 31-40. [cited by applicant]
Trotta et al. “A human anti-IL-2 antibody that potentiates regulatory T cells by a structure-based mechanism.” Nature medicine 24, No. 7 (2018): 1005-1014. [cited by applicant]
Vincenti, et al. “Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation.” New England Journal of Medicine 338, No. 3 (1998): 161-165. [cited by applicant]
Wada, et al. “Codon usage tabulated from the GenBank genetic sequence data.” Nucleic acids research 20, No. Suppl (1992): 2111. [cited by applicant]
Waldmann, et al. “Phase 1 trial of IL-15 trans presentation blockade using humanized Mik-Beta-1 mAb in patients with T-cell large granular lymphocytic leukemia.” Blood, The Journal of the American Society of Hematology … [cited by applicant]
Wang, Wei, Y. John Wang, and D. Q. Wang. “Dual effects of Tween 80 on protein stability.” International journal of pharmaceutics 347, No. 1-2 (2008): 31-38. [cited by applicant]
Wang, Alice, Shi-Da Lu, and David F. Mark. “Site-specific mutagenesis of the human interleukin-2 gene: structure-function analysis of the cysteine residues.” Science 224, No. 4656 (1984): 1431-1433. [cited by applicant]
Wang, Xinquan, Mathias Rickert, and K. Christopher Garcia. “Structure of the Quaternary Complex of Interleukin-2 with Its α, β, and γc Receptors.” Science 310, No. 5751 (2005): 1159-1163. [cited by applicant]
Wittrup, K. Dane. “Antitumor antibodies can drive therapeutic T cell responses.” Trends in cancer 3, No. 9 (2017): 615-620. [cited by applicant]
Wrangle, John M., Alicia Patterson, C. Bryce Johnson, Daniel J. Neitzke, Shikhar Mehrotra, Chadrick E. Denlinger, Chrystal M. Paulos, Zihai Li, David J. Cole, and Mark P. Rubinstein. “IL-2 and beyond in cancer immunothe… [cited by applicant]
Xia, Haibin, Qinwen Mao, Henry L. Paulson, and Beverly L. Davidson. “siRNA-mediated gene silencing in vitro and in vivo.” Nature biotechnology 20, No. 10 (2002): 1006-1010. [cited by applicant]
Zalipsky, Samuel. “Functionalized poly (ethylene glycols) for preparation of biologically relevant conjugates.” Bioconjugate chemistry 6, No. 2 (1995): 150-165. [cited by applicant]
Zorn, E., Nelson, E.A., Mohseni, M., Porcheray, F., Kim, H., Litsa, D., Bellucci, R., Raderschall, E., Canning, C., Soiffer, R.J. and Frank, D.A., 2006. IL-2 regulates FOXP3 expression in human CD4+ CD25+ regulatory T c… [cited by applicant]
Zurawski SM, Zurawski G. Identification of three critical regions within mouse interleukin 2 by fine structural deletion analysis. The EMBO journal. Apr. 1988;7(4):1061-9. [cited by applicant]
Zurawski SM, Zurawski G. Receptor antagonist and selective agonist derivatives of mouse interleukin-2. The EMBO journal. Nov. 1992;11(11):3905-10. [cited by applicant]
International Search Report and Written Opinion in PCT/US2021/013456, mailed Jul. 22, 2021, 15 pages. [cited by applicant]
Kaplan et al., “Demonstration of an interferon γ-dependent tumor surveillance system in immunocompetent mice,” Proc. Natl. Acad. Sci. USA, vol. 95, Jun. 1998, pp. 7556-7561. [cited by applicant]
Bluestone, et al. (2015) IL2: Change Structure . . . Change Function Immunity 42:779-781. [cited by applicant]
Bradhuber, et al. (1987) J. Biol Chem 25(2):12306-12308. [cited by applicant]
Carnemolla, et al (2002) Enhancement of the antitumor properties of interleukin-2 by its targeted delivery to the tumor blood vessel extracellular matrix ; Blood 99(5) :1659-1665. [cited by applicant]
Gaffen et al. Distinct tyrosine residues within the interleukin-2 receptor β chain drive signal transduction specificity, redundancy, and diversity. Journal of Biological Chemistry. Aug. 30, 1996;271(35):21381-90. [cited by applicant]
Gerhartz et al. Differential activation of acute phase response factor/STAT3 and STAT1 via the cytoplasmic domain of the interleukin 6 signal transducer gp130: I. Definition of a novel phosphotyrosine motif mediating ST… [cited by applicant]
Ghasemi, et al (2016) Selective targeting of IL-2 to NKG2D bearing cells for improved immunotherapy; Nature Communications 7:12878 | DOI: 10.1038/ncomms12878 |. [cited by applicant]
Hargadon, et al. “Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors.” International immunopharmacology 62 (2018): 29-39. [cited by applicant]
He, et al (2016) Low-dose interleukin-2 treatment selectively modulates CD4+ T cell subsets in patients with systemic lupus erythematosus Nature Medicine 22(9):991-993. [cited by applicant]