IP Library Granted Patent US 12,522,639
Granted Patent B2
US 12,522,639 · App. 18/516,047 · Granted Jan 13, 2026

Heterodimeric FC cytokines and uses thereof

Inventors: Patrick Lupardus (Menlo Park, CA); Deepti Rokkam (Menlo Park, CA)
Assignee: Synthekine, Inc.
C07K14/5434A61K45/06A61P35/00A61K38/00
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 12,522,639
App. No.
18/516,047
Granted
Jan 13, 2026
Kind
B2
Abstract

The present disclosure provides IL12 and IL23 muteins as partial agonists comprising modified human p40 molecules that associate with human p35 (hP35) and human P19 (hP19) to form modified hIL-12 and IL23 partial agonists wherein the individual components of IL12 and IL23 muteins are linked to engineered Fc domains.

Claims (20)

1 . A method of treating a mammal suffering from a neoplastic disease the method comprising the step of contacting the mammal with a pharmaceutically acceptable formulation comprising as an active ingredient a heterodimeric hIL12Fc mutein, wherein the heterodimeric hIL 12Fc mutein comprising a first polypeptide having the sequence of any one of SEQ ID NOS: 80, 83, 85, 86, 88, 90, 92, 121, 129, 132, 135, 138, 141, 144, 147, 150, and 153; and

a second polypeptide having the sequence of any one of SEQ ID NOS: 81, 82, 84, 87, 89, 91, 93, and 124.

2 . The method of claim 1 , wherein the dose of the heterodimeric hIL 12Fc mutein provided to the mammal is from 10 μg/kg to 500 μg/kg.

3 . The method of claim 1 , the method further comprising the step of contacting the mammal in combination with one or more supplementary therapeutic agents.

4 . The method of claim 3 , wherein one or more supplementary therapeutic agents supplementary therapeutic agent is selected from the group consisting of checkpoint inhibitors, cytokines, or a therapeutic antibody.

5 . The method of claim 1 , wherein the neoplastic disease is characterized by a tumor with T cell infiltration.

6 . The method of claim 1 , wherein the neoplastic disease is selected from the group consisting of melanoma, renal cell carcinoma (RCC), ovarian cancer, cervical cancer, non-small cell lung cancer (NSCLC), head and neck cancer, pancreatic cancer, and microsatellite instability (MSI) high cancers.

7 . The method of claim 1 , wherein the first polypeptide has the sequence of SEQ ID NO: 80 and the second polypeptide has the sequence of SEQ ID NO: 81.

8 . The method of claim 1 , wherein the first polypeptide has the sequence of SEQ ID NO: 121 and the second polypeptide has the sequence of SEQ ID NO: 124.

9 . The method of claim 1 , wherein the first polypeptide has the sequence of SEQ ID NO: 83 and the second polypeptide has the sequence of SEQ ID NO: 82.

10 . The method of claim 1 , wherein the first polypeptide has the sequence of SEQ ID NO: 141 and the second polypeptide has the sequence of SEQ ID NO: 124.

11 . The method of claim 1 , wherein the first polypeptide has the sequence of SEQ ID NO:144 and the second polypeptide has the sequence of SEQ ID NO: 124.

12 . The method of claim 1 , wherein the first polypeptide has the sequence of SEQ ID NO: 129 and the second polypeptide has the sequence of SEQ ID NO: 124.

13 . The method of claim 1 , wherein the first polypeptide has the sequence of SEQ ID NO: 147 and the second polypeptide has the sequence of SEQ ID NO: 82.

14 . The method of claim 1 , wherein the first polypeptide has the sequence of SEQ ID NO: 150 and the second polypeptide has the sequence of SEQ ID NO: 82.

15 . The method of claim 1 , wherein the first polypeptide has the sequence of SEQ ID NO: 153 and the second polypeptide has the sequence of SEQ ID NO: 82.

16 . The method of claim 1 , wherein the first polypeptide has the sequence of SEQ ID NO: 135 and the second polypeptide has the sequence of SEQ ID NO: 124.

17 . The method of claim 1 , wherein the first polypeptide has the sequence of SEQ ID NO: 138 and the second polypeptide has the sequence of SEQ ID NO: 124.

18 . The method of claim 1 , wherein the first polypeptide and the second polypeptide are linked by at least one interchain disulfide bond.

19 . The method of claim 1 , wherein the heterodimeric hIL 12Fc mutein is PEGylated.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 27, 2023
From: LUPARDUS, PATRICK; ROKKAM, DEEPTI
To: SYNTHEKINE, INC.
Reel/Frame 065667/0539 →
Continuity (3)
Continuation PCTUS2022078465 · Oct 20, 2022
Provisional Application 63257913 · Oct 20, 2021
Related Publication 20240132562A1 · Apr 25, 2024
References Cited (315)
US 5731168A · Carter et al. · 1998 [cited by applicant]
US 5756085A · Sykes et al. · 1998 [cited by applicant]
US 5891680A · Lieschke et al. · 1999 [cited by applicant]
US 6682736B1 · Hanson et al. · 2004 [cited by applicant]
US 6838260B2 · Gillies et al. · 2005 [cited by applicant]
US 6984720B1 · Korman et al. · 2006 [cited by applicant]
US 7045337B2 · Schultz et al. · 2006 [cited by applicant]
US 7141651B2 · Gillies et al. · 2006 [cited by applicant]
US 7404956B2 · Peters et al. · 2008 [cited by applicant]
US 7576193B2 · Gillies et al. · 2009 [cited by applicant]
US 7872107B2 · Webster et al. · 2011 [cited by applicant]
US 7879319B2 · Gillies et al. · 2011 [cited by applicant]
US 7915025B2 · Schultz et al. · 2011 [cited by applicant]
US 7943743B2 · Korman et al. · 2011 [cited by applicant]
US 8008449B2 · Korman et al. · 2011 [cited by applicant]
US 8168757B2 · Finnefrock et al. · 2012 [cited by applicant]
US 8217149B2 · Irving et al. · 2012 [cited by applicant]
US 8367805B2 · Chamberlain et al. · 2013 [cited by applicant]
US 8394925B2 · Chamberlain et al. · 2013 [cited by applicant]
US 8546543B2 · Lazar · 2013 [cited by applicant]
US 8592562B2 · Kanaan et al. · 2013 [cited by applicant]
US 8927518B1 · Heller et al. · 2015 [cited by applicant]
US 9527926B2 · Ho et al. · 2016 [cited by applicant]
US 9562109B2 · Von Kreudenstin et al. · 2017 [cited by applicant]
US 10336818B2 · Chamberlain et al. · 2019 [cited by applicant]
US 10494437B2 · Niwa et al. · 2019 [cited by applicant]
US 10696722B2 · Kim et al. · 2020 [cited by applicant]
US 10696723B2 · Winston et al. · 2020 [cited by applicant]
US 11078249B2 · Kim et al. · 2021 [cited by applicant]
US 11087249B2 · Leonelli et al. · 2021 [cited by applicant]
US 11358999B2 · Bernett et al. · 2022 [cited by applicant]
US 11401348B2 · Lazar et al. · 2022 [cited by applicant]
US 12103954B2 · Lupardus · 2024 [cited by examiner]
US 20040223969A1 · Oft et al. · 2004 [cited by applicant]
US 20100196315A1 · Lacy et al. · 2010 [cited by applicant]
US 20120100140A1 · Reyes et al. · 2012 [cited by applicant]
US 20180185515A1 · Hicklin et al. · 2018 [cited by applicant]
US 20200032506A1 · Slättberg et al. · 2020 [cited by applicant]
US 20200325206A1 · Mahr et al. · 2020 [cited by applicant]
US 20200362005A1 · Kim et al. · 2020 [cited by applicant]
US 20210355185A1 · Bernett et al. · 2021 [cited by applicant]
US 20220119533A1 · Cheung et al. · 2022 [cited by applicant]
US 20220372495A1 · Schmidt et al. · 2022 [cited by applicant]
US 20230220031A1 · Garcia et al. · 2023 [cited by applicant]
US 20240132562A1 · Lupardus et al. · 2024 [cited by applicant]
WO 9205256A1 · 1992 [cited by applicant]
WO 2004081190A2 · 2004 [cited by applicant]
WO 2014145907A1 · 2014 [cited by applicant]
WO 2015124297A1 · 2015 [cited by applicant]
WO 2016048903A1 · 2016 [cited by applicant]
WO 2018148445A1 · 2018 [cited by applicant]
WO 2019149039A1 · 2019 [cited by applicant]
WO 2019157332A1 · 2019 [cited by applicant]
WO 2019209965A2 · 2019 [cited by applicant]
WO 20200072821A3 · 2020 [cited by applicant]
WO 2020072821A2 · 2020 [cited by applicant]
WO 2020086758A1 · 2020 [cited by applicant]
WO 2021016640A1 · 2021 [cited by applicant]
WO 2021067863A2 · 2021 [cited by applicant]
WO 2021146436A2 · 2021 [cited by applicant]
WO 2021146481A1 · 2021 [cited by applicant]
WO 2021212083A2 · 2021 [cited by applicant]
WO 2021216916A1 · 2021 [cited by applicant]
WO 2023070038A2 · 2023 [cited by applicant]
Bryson S and Mulne A “Blood and Neoplastic Disorders” Pediatric Board Strudy Guide, O. Naga (ed), p. 343-371 (Year: 2015). [cited by examiner]
Application No. PCT/US2022/078465 , International Search Report and Written Opinion, Mailed On Jul. 11, 2023, 14 pages. [cited by applicant]
PCT/US2022/078465 , “Invitation to Pay Additional Fees and, Where Applicable, Protest Fee”, Apr. 3, 2023, 3 pages. [cited by applicant]
Altschul, et al., “Basic local alignment search tool.” Journal of molecular biology 215, No. 3 (1990): 403-410. [cited by applicant]
Ahn, et al., “136O: Osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer: Results from the TATTON phase Ib trial.” Journal of Thoracic Oncology 11, No. 4 (2016): S115. [cited by applicant]
Atkins, et al., “Phase 1 Evaluation of Intravenous Recombinant Human Interleukin 12 in Patients with Advanced Malignancies,” Clinical Cancer Research (1997) 3:409-417. [cited by applicant]
Anderson, et al., “Construction and Biological Characterization of an Interleukin-12 Fusion Protein (Flexi-12): Delivery to Acute Myeloid Leukemic Blasts Using Adeno-associated Virus,” Human Gene Therapy (1997) 8:1125-1… [cited by applicant]
Ardolino, et al., “Cytokine Therapy Reverses Nk Cell Anergy in Mhc-deficient Tumors,” The Journal of Clinical Investigation (2014) 24(11):4781-4794. [cited by applicant]
Aste-Amezaga, et al., “Cooperation of Natural Killer Cell Stimulatory Factor/interleukin-12 with Other Stimuli in the Induction of Cytokines and Cytotoxic Cell-associated Molecules in Human T and Nk Cells,”Cell Immunol … [cited by applicant]
Atwell, et al., “Stable Heterodimers from Remodeling the Domain Interface of a Homodimer using a Phage Display Library,” J. Mol. Biol. (1997) 270, 26±35. [cited by applicant]
Bastian, et al., “The IL-12 Cytokine and Receptor Family in Graft-vs.-Host Disease,” Frontiers in Immunology (2019) vol. 10 Article 988. [cited by applicant]
Bekaii-Saab, et al., “A Phase I Trial of Paclitaxel and Trastuzumab in Combination With Interleukin-12 in Patients With Her2/neu-expressing Malignancies,” Molecular Cancer Therapeutics (2009) 8(11):2983-2991. [cited by applicant]
Belladonna et al., “Bioengineering heterodimeric cytokines: turning promiscuous proteins into therapeutic agents,” (2013) Biotechnology and Genetic Engineering Reviews, 29:2, 149-174. [cited by applicant]
Benson, et al. “Therapeutic Targeting of the II-12/23 Pathways:Generation and Characterization of Ustekinumab,” Nature Biotechnology (2011) 29(7):615-624. [cited by applicant]
Bernett et al., “Potency-Reduced and Extended Half-Life IL12 Heterodimeric Fc-Fusions Exhibit Strong Anti-Tumor Activity With Potentially Improved Therapeutic Index Compared to Native IL12 Agents,” J Immunother Cancer 2… [cited by applicant]
Bernett, et al., “IL12d potency exhibit strong anti-tumor activity and improved therapeutic index compared to compared to native IL12 agents,” 2021 AACR Abstract #1743. [cited by applicant]
Bloch, et al., “Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1,” Cell (2018) 48:45-58(1-14). [cited by applicant]
Boulanger, et al., “Convergent Mechanisms for Recognition of Divergent Cytokines by the Shared Signaling Receptor Gp130,” Molecular Cell (2003) 12:577-589. [cited by applicant]
Boulanger, et al., “Hexameric Structure and Assembly Of The Interleukin-6/il-6 Alpha-receptor/gp130 Complex,” Science (2003) 300:2101-2104. [cited by applicant]
Brekke et al., “Structure-Function Relationships of Human IgG,” The Immunologist, 2/4, 1994, pp. 125-130. [cited by applicant]
Brunda, et al., “Antitumor And Antimetastatic Activity Of Interleukin 12 Against Murine Tumors,” Journal of Experimental Medicine (1993) 178:1223-30. [cited by applicant]
Caceci, et al., “Fitting curves to data.” Byte 9, No. 5 (1984): 340-362. [cited by applicant]
Carmenate et al., “Human IL-2 Mutein with Higher Antitumor Efficacy Than Wild Type IL-2”, Journal of Immunology, vol. 190, No. 12, 2013, pp. 6230-6238. [cited by applicant]
Cartellieri, et al., “Chimeric antigen receptor-engineered T cells for immunotherapy of cancer.” BioMed Research International 2010, No. 1 (2010): 956304. [cited by applicant]
Carter, et al., “Bispecific Human IgG by Design,” Journal of Immunological Methods (2001) 248(1-2):7-15. [cited by applicant]
Chao, et al., “Isolating and engineering human antibodies using yeast surface display,” Nature Protocols (2006) 1(2):755-768. [cited by applicant]
Chappel, et al., “Identification of the Fc, receptor class I binding site in human IgG through the use of recombinant IgG1/IgG2 hybrid and point-mutated antibodies,” PNAS USA (1991) vol. 88,pp. 9036-9040. [cited by applicant]
Cheadle, et al. “CAR T cells: driving the road from the laboratory to the clinic.” Immunological reviews 257, No. 1 (2014): 91-106. [cited by applicant]
Choudhary, et al., “Lysine Acetylation Targets Protein Complexes and Co-Regulates Major Cellular Functions,” Science (2009) 325(5942): 834-840. [cited by applicant]
Chua, et al., “Expression Cloning Of A Human II-12 Receptor Component. A New Member of The Cytokine Receptor Superfamily with Strong Homology to gp130,” The Journal of Immunology (1994) 153(1):128-136. [cited by applicant]
Collison, et al., “The Inhibitory Cytokine II-35 Contributes to Regulatory T-cell Function,” Nature (2007) 450:566-569. [cited by applicant]
Cooper, et al., “Mice Lacking Bioactive II-12 Can Generate Protective, Antigen-specific Cellular Responses to Mycobacterial Infection Only if the II-12 P40 Subunit is Present,” The Journal of Immunology (2002) 168(3):13… [cited by applicant]
Curran, et al., “Chimeric antigen receptors for T cell immunotherapy: current understanding and future directions.” The journal of gene medicine 14, No. 6 (2012): 405-415. [cited by applicant]
Decken, et al., “Interleukin-12 is Essential for a Protective Th1 Response in Mice Infected With Cryptococcus Neoformans,” Infection and immunity(1998) 66(10): 4994-5000. [cited by applicant]
Deiters, et al., “Site-specific PEGylation of Proteins Containing Unnatural Amino Acids,” Bioorganic & Medicinal Chemistry Letters (2004) 14(23):5743-5745. [cited by applicant]
Delano, et al., “Convergent Solutions To Binding At A Protein-protein Interface,” Science (2002) 287:1279-1283. [cited by applicant]
Desmyter, et al., “Neutralization Of Human Interleukin 23 By Multivalent Nanobodies Explained By The Structure Of Cytokine-nanobody Complex,” Frontiers in Immunology (2017) 8:884(1-10). [cited by applicant]
Devereux, et al. “A comprehensive set of sequence analysis programs for the VAX.” (1984): 387-395. [cited by applicant]
Dorai, et al., “Role of Inter-Heavy and Light Chain Disulfide Bonds in the Effector Functions of Human Immunoglobulin IgGI,” Molecular Immunol (1992) vol. 29, No. 12,pp. 1487-1491. [cited by applicant]
Dozier, et al., “Site-Specific PEGylation of Therapeutic Proteins,” International Journal of Molecular Science (2015) 16(10):25831-25864. [cited by applicant]
Economides, et al., “Cytokine traps: multi-component, high-affinity blockers of cytokine action,” Nature Medicine (2003) 9(1) , 47-52. [cited by applicant]
Eyquem, et al., “Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection.” Nature 543, No. 7643 (2017): 113-117. [cited by applicant]
Fedorov, et al., “PD-1—and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses.” Science translational medicine 5, No. 215 (2013): 215ra172-215ra172. [cited by applicant]
Fewell, et al., “Treatment of Disseminated Ovarian Cancer Using Nonviral Interleukin-12 Gene Therapy Delivered Intraperitoneally,” The Journal of Gene Medicine (2009) 11:718-728. [cited by applicant]
Foss, et al., “In Vitro and In Vivo Bioactivity of Single-Chain Interleukin-12,” Scand. J. Immunol (1999) 50, 596-604. [cited by applicant]
Fridman et al., “The Use of Cytokines in the Treatment of Solid Tumours”, Hematology and Cell Therapy, vol. 39, No. 2, 1997, pp. 105-108. [cited by applicant]
Application No. PCT/US2022/078465 , International Preliminary Report on Patentability, Mailed On May 2, 2024, 10 pages. [cited by applicant]
Application No. PCT/US2023/077331 , International Search Report and the Written Opinion, Mailed On Feb. 26, 2024, 15 pages. [cited by applicant]
Gafner, et al., “An engineered antibody-interleukin-12 fusion protein with enhanced tumor vascular targeting properties,” Int. J. Cancer: 119, 2205-2212 (2006). [cited by applicant]
Genestier, et al., “Transforming growth factor β1 inhibits Fas ligand expression and subsequent activation-induced cell death in T cells via downregulation of c-Myc.” The Journal of experimental medicine 189, No. 2 (199… [cited by applicant]
Georgiadis, et al. “Long terminal repeat CRISPR-CAR-coupled “universal” T cells mediate potent anti-leukemic effects.” Molecular Therapy 26, No. 5 (2018): 1215-1227. [cited by applicant]
Georgy, et al., “Tryptophan (W) at position 37 of murine IL-12/IL-23 p40 is mandatory for binding to IL-12Rβ1 and subsequent signal transduction,” J. Biol. Chem. (2021) 297(5) 101295. [cited by applicant]
Gillies, et al., “Antibody-IL-12 Fusion Proteins Are Effective in SCID Mouse Models of Prostate and Colon Carcinoma Metastases,” The Journal of Immunology, 1998, 160: 6195-6203. [cited by applicant]
Gillies, et al., “Bi-functional cytokine fusion proteins for gene therapy and antibody-targeted treatment of cancer,” Cancer Immunol Immunother (2002) 51: 449-460. [cited by applicant]
Glassman, et al., “Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells,” Cell (2021) 184, 983-999. [cited by applicant]
Glienke, et al. “Advantages and applications of CAR-expressing natural killer cells.” Frontiers in pharmacology 6 (2015): 21. [cited by applicant]
Goldberg, et al. “LAG-3 in cancer immunotherapy.” Cancer immunology and immunotherapy (2011): 269-278. [cited by applicant]
Graham, et al. “Allogeneic CAR-T cells: more than ease of access?.” Cells 7, No. 10 (2018): 155. [cited by applicant]
Gross, et al. “Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity.” Proceedings of the National Academy of Sciences 86, No. 24 (1989): 10024-10028. [cited by applicant]
Grosso, et al. “LAG-3 regulates CD8+ T cell accumulation and effector function in murine self-and tumor-tolerance systems.” The Journal of clinical investigation 117, No. 11 (2007): 3383-3392. [cited by applicant]
Ho, et al., “Immunoglobulin Fc Heterodimer Platform Technology: From Design to Applications in Therapeutic Antibodies and Proteins,” Front. Immunol.(2016) vol. 7 | Article 394. [cited by applicant]
Hogquist, et al. “T cell receptor antagonist peptides induce positive selection.” Cell 76, No. 1 (1994): 17-27. [cited by applicant]
Holscher, et al. “A protective and agonistic function of IL-12p40 in mycobacterial infection.” The Journal of Immunology 167, No. 12 (2001): 6957-6966. [cited by applicant]
Huyton, et al. “An unusual cytokine: Ig-domain interaction revealed in the crystal structure of leukemia inhibitory factor (LIF) in complex with the LIF receptor.” Proceedings of the National Academy of Sciences 104, No… [cited by applicant]
Idziorek, et al. “Recombinant human IL-16 inhibits HIV-1 replication and protects against activation-induced cell death (AICD).” Clinical & Experimental Immunology 112, No. 1 (1998): 84-91. [cited by applicant]
Jensen, et al. “Designing chimeric antigen receptors to effectively and safely target tumors.” Current opinion in immunology 33 (2015): 9-15. [cited by applicant]
Ji et al., “Synergistic Anti-tumor Effect of Glycosylphosphatidylinositol-anchored IL-2 and IL-12”, The Journal of Gene Medicine, vol. 6, No. 7, 2004, pp. 777-785. [cited by applicant]
Jiang et al., “Sustained Expression of Fc-Fusion Cytokine Following In Vivo Electroporation and Mouse Strain Differences in Expression Level,” Biochem. (2003)133: 423-427. [cited by applicant]
Jung et al., “Heterodimeric Fc-fused IL12 shows potent antitumor activity by generating memory CD8 T cells,” Oncoimmunology 2018, vol. 7, No. 7, e1438800. [cited by applicant]
Kabsch, Wolfgang. “xds.” Acta Crystallographica Section D: Biological Crystallography 66, No. 2 (2010): 125-132. [cited by applicant]
Kakarla, et al. “CAR T cells for solid tumors: armed and ready to go?.” The Cancer Journal 20, No. 2 (2014): 151-155. [cited by applicant]
Kobayashi, et al. Identification and Purification of Natural Killer Cell Stimulatory Factor (NKSF), a Cytokine with Multiple Biologic Effects on Human Lymphocytes Journal of Experimental Medicine (1989) 170(3):827-845. [cited by applicant]
Kontermann “Half-life extended biotherapeutics,” Expert Opinion on Biological Therapy(2016) 16(7): 903-915. [cited by applicant]
Kopp, et al., “Clinical Improvement in Psoriasis With Specific Targeting of Interleukin-23,” Nature (2015) 521:222-226(1-15). [cited by applicant]
Koutruba, et al. “Review of Ustekinumab, an Interleukin-12 and Interleukin-23 Inhibitor Used for the Treatment Of Plaque Psoriasis,” Therapeutics and Clinical Risk Management (2010) 6:123-141. [cited by applicant]
Kundu, et al. “Selective neutralization of IL-12 p40 monomer induces death in prostate cancer cells via IL-12-IFN-γ.” Proceedings of the National Academy of Sciences 114, No. 43 (2017): 11482-11487. [cited by applicant]
Lasek, et al., “Interleukin 12: Still a Promising Candidate for Tumor Immunotherapy?” Cancer Immunol Immunother (2014) 63:419-35. [cited by applicant]
Leahy, et al. “Structure of a fibronectin type III domain from tenascin phased by MAD analysis of the selenomethionyl protein.” Science 258, No. 5084 (1992): 987-991. [cited by applicant]
Leong et al., “Optimized expression and specific activity of IL-12 by directed molecular evolution,” PNAS Feb. 4, 2003 vol. 100 No. 3 1163-1168. [cited by applicant]
Liang, et al., “IL-23 Receptor Expression on γδT Cells Correlates with Their Enhancing or Suppressive Effects on Autoreactive T Cells in Experimental Autoimmune Uveitis,” The Journal of Immunology (2013) 191(3):1118-112… [cited by applicant]
Lieschke et al., “Biactive murine and human interleukin-12 fusion proteins which retain antitumor activity in vivo,” Nature Biotechnology (1997) 16:35. [cited by applicant]
Littman, et al., “Th17 and Regulatory T Cells in Mediating and Restraining Inflammation,” Cell (2010) 140:845-858. [cited by applicant]
Li-Weber, et al. “Vitamin E inhibits CD95 ligand expression and protects T cells from activation-induced cell death.” The Journal of clinical investigation 110, No. 5 (2002): 681-690. [cited by applicant]
Lo, et al., “Effector-attenuating Substitutions That Maintain Antibody Stability and Reduce Toxicity in Mic,” J Biological Chermistry vol. 292 ⋅ No. 9 ⋅ Mar. 3, 2017. [cited by applicant]
Low, et al., “Oral and pulmonary delivery of FSH-Fc fusion proteins via neonatal Fc receptor-mediated transcytosis,” Human Reproduction (2005) 20(7):1805-1813. [cited by applicant]
Luo et al., Structural Basis for the Dual Recognition of II-12 and II-23 by Ustekinumab Journal of Molecular Biology (2010) 402:797-812. [cited by applicant]
Lupardus, et al. The Structure of Interleukin-23 Reveals the Molecular Basis of P40 Subunit Sharing With Interleukin-12, Journal Of Molecular Biology (2008) 382(4):931-941. [cited by applicant]
Matrosovich, et al. “Solid-phase assays of receptor-binding specificity.” Influenza Virus: Methods and Protocols (2012): 71-94. [cited by applicant]
Mattner, et al., “Genetically Resistant Mice Lacking Interleukin-12 Are Susceptible to Infection With Leishmania Major and Mount a Polarized Th2 Cell Response,” European Journal of Immunology (1996) 26:1553-1559. [cited by applicant]
Merchant et al., “An efficient route to human bispecific IgG,” Nature Biotechnology vol. 16:677 Jul. 1998. [cited by applicant]
Morin, et al. “Collaboration gets the most out of software.” elife 2 (2013): e01456. [cited by applicant]
Moore et al., “A robust heterodimeric Fc platform engineered for efficient development of bispecific antibodies of multiple formats,” Methods 154 (2019) 38-50. [cited by applicant]
Morrison, et al. “Structural determinants of human IgG function.” The Immunologist 2, No. 4 (1994): 119-124. [cited by applicant]
Munson, et al. “Ligand: a versatile computerized approach for characterization of ligand-binding systems.” Analytical biochemistry 107, No. 1 (1980): 220-239. [cited by applicant]
Murray, “The JAK-STAT Signaling Pathway: Input and Output Integration,” Journal of Immunology (2007) 178(5):2623-2629. [cited by applicant]
Nguyen et al., “Localized Interleukin-12 for Cancer Immunotherapy,” Frontiers in Immunology (2020) Article#575597. [cited by applicant]
Oh, et al. “Secretion of recombinant interleukin-22 by engineered Lactobacillus reuteri reduces fatty liver disease in a mouse model of diet-induced obesity.” MSphere 5, No. 3 (2020): 10-1128. [cited by applicant]
Oppmann, et al. “Novel P19 Protein Engages II-12p40 to Form a Cytokine, II-23, With Biological Activities Similar as Well as Distinct From II-12,” Cell (2000) 13:715-725. [cited by applicant]
Pardoll, Drew M. “The blockade of immune checkpoints in cancer immunotherapy.” Nature reviews cancer 12, No. 4 (2012): 252-264. [cited by applicant]
Parham, et al., “A Receptor for the Heterodimeric Cytokine II-23 is Composed of II-12rbeta1 and a Novel Cytokine Receptor Subunit, II-23r,” The Journal of Immunology (2002) 168(11):5699-5708. [cited by applicant]
Pasche, et al., “The Antibody-based Delivery of Interleukin-12 to the Tumor Neovasculature Eradicates Murine Models of Cancer in Combination With Paclitaxel,” Cancer Therapy: Preclinical (2012) 18(15):4092-4103. [cited by applicant]
Application No. PCT/US2021/027838, International Search Report and Written Opinion, mailed Oct. 31, 2021, 12 pages. [cited by applicant]
Application No. PCT/US2022/078439, International Search Report and Written Opinion, mailed Jul. 10, 2023, 12 pages. [cited by applicant]
Application No. PCT/US2022/078465 , “Invitation to Pay Additional Fees and, Where Applicable, Protest Fee”, Apr. 3, 2023, 3 pages. [cited by applicant]
Pegram, et al., “Tumor-targeted T Cells Modified to Secrete II-12 Eradicate Systemic Tumors Without Need for Prior Conditioning,” Blood (2012)119(18):4133-4141. [cited by applicant]
Pegram, et al. “CD28z cars and armored cars.” The Cancer Journal 20, No. 2 (2014): 127-133. [cited by applicant]
Peng et al., “A Single-Chain IL-12 IgG3 Antibody Fusion Protein Retains Antibody Specificity and IL-12 Bioactivity and Demonstrates Antitumor Activity,” The Journal of Immunology, 1999, 163: 250-258. [cited by applicant]
Pflanz, et al. “IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells.” Immunity 16, No. 6 (2002): 779-790. [cited by applicant]
Presky, et al., “A Functional Interleukin 12 Receptor Complex is Composed of Two Beta-type Cytokine Receptor Subunits,” Proceedings of the National Academy of Sciences (1996) 93(24):14002-14007. [cited by applicant]
Rath et al., “Fc-fusion proteins and FcRn: structural insights for longer-lasting and more effective therapeutics,” Crit Rev Biotechnol, Early Online: 1-20. [cited by applicant]
Riddell, et al. “Adoptive therapy with chimeric antigen receptor-modified T cells of defined subset composition.” The Cancer Journal 20, No. 2 (2014): 141-144. [cited by applicant]
Ridgway, et al., ‘Knobs-into-holes’ Engineering of Antibody Ch3 Domains for Heavy Chain Heterodimerization, Protein Engineering, Design and Selection (1996) 9(7):617-621. [cited by applicant]
Riethmueller, et al. “Proteolytic origin of the soluble human IL-6R in vivo and a decisive role of N-glycosylation.” PLoS biology 15, No. 1 (2017): e2000080. [cited by applicant]
Rossjohn, et al. “T cell antigen receptor recognition of antigen-presenting molecules.” Annual review of immunology 33, No. 1 (2015): 169-200. [cited by applicant]
Sadelain, et al. “The basic principles of chimeric antigen receptor design.” Cancer discovery 3, No. 4 (2013): 388-398. [cited by applicant]
Sambrook, et al. Molecular cloning: a laboratory manual. vol. 1, No. Ed. 4. 2012, 34 pages. [cited by applicant]
Sasikumar, et al. “Oral immune checkpoint antagonists targeting PD-L1/VISTA or PD-L1/Tim3 for cancer therapy.” In AACR annual meeting. 2016. [cited by applicant]
Scallon et al., “Quantitative in vivo comparisons of the Fcγ receptor-dependent agonist activities of different fucosylation variants of an immunoglobulin G antibody,” International Immunopharmacology (2007) 7:761-772. [cited by applicant]
Schlothauer et al., “Novel human IgG1 and IgG4 Fc-engineered antibodies with completely abolished immune effector functions,” Protein Engineering, Design & Selection, 2016, vol. 29 No. 10, pp. 457-466. [cited by applicant]
Schmidt, “Fusion proteins as biopharmaceuticals—Applications and challenges,” Current Opinion in Drug Discovery & Development 2009 12(2): 1367-6733. [cited by applicant]
Schroder, et al. Non-canonical Interleukin 23 Receptor Complex Assembly: P40 Protein Recruits Interleukin 12 Receptor B1 via Site Ii and Induces P19/interleukin 23 Receptor Interaction via Site III Journal of Biological… [cited by applicant]
Schulich, et al., “The Third Signal Cytokine II-12 Rescues the Anti-viral Function of Exhausted Hbv-specific Cd8 T Cells,” PLOS Pathogens, e1003208 9(3):1-12. [cited by applicant]
Shi, et al., Cyclos[orin A Inhibits Activation-Induced Cell Death in T-Cell Hybridomas andThymocytes, Nature, vol. 339, Jun. 22, 1989, 625-626. [cited by applicant]
Skiniotis, et al., “Structural Organization of a Full-length Gp130/lif-r Cytokine Receptor Transmembrane Complex,” Molecular Cell (2008) 31:737-748. [cited by applicant]
Skrombolas, et al., “Characterization of an IL-12 p40/p35 Truncated Fusion Protein That Can Inhibit the Action of IL-12,” Journal of Interferon & Cytokine Research vol. 35, No. 9, 2015. [cited by applicant]
Steidler, et al. “Biological containment of genetically modified Lactococcus lactis for intestinal delivery of human interleukin 10.” Nature biotechnology 21, No. 7 (2003): 785-789. [cited by applicant]
Strohl, “Optimization of Fc-mediated effector functions of monoclonal antibodies,” Current Opinion in Biotechnology 2009, 20:685-691. [cited by applicant]
Szabo, et al. “Regulation of the interleukin (IL)-12R β2 subunit expression in developing T helper 1 (Th1) and Th2 cells.” The Journal of experimental medicine 185, No. 5 (1997): 817-824. [cited by applicant]
Takeshita, et al. “Cloning of the γ chain of the human IL-2 receptor.” Science 257, No. 5068 (1992): 379-382. [cited by applicant]
Tamura, et al., “Intratumoral Delivery of Interleukin 12 Expression Plasmids With in Vivo Electroporation is Effective for Colon and Renal Cancer,” Human Gene Therapy (2001) 12:1265-1276. [cited by applicant]
Thul, et al. “A subcellular map of the human proteome.” Science 356, No. 6340 (2017): eaal3321. [cited by applicant]
Trinchieri, “Interleukin-12 and the Regulation of Innate Resistance and Adaptive Immunity,” Nature Reviews Immunology (2003) 3(2):133-146. [cited by applicant]
Tseng, et al. “Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response.” Proceedings of the National Academy of Sciences 110, No. 27 (2013): 11103-11108. [cited by applicant]
Tugues et al., “New insights into IL-12-mediated tumor suppression,” Cell Death and Differentiation (2015) 22, 237-246. [cited by applicant]
Valeich et al., “Taking the Hinge off: An Approach to Effector-Less Monoclonal Antibodies,” Antibodies {2020), 9: 50. [cited by applicant]
Vance, et al. “Listening to each other: Infectious disease and cancer immunology.” Science immunology 2, No. 7 (2017): eaai9339. [cited by applicant]
Vazquez-Lombardi et al., “Molecular Engineering of Therapeutic Cytokines,” Antibodies (2013) 2: 426-451. [cited by applicant]
Vignali, et al., “II-12 Family Cytokines: Immunological Playmakers,” Nature Immunology (2012) 13(8):722-728. [cited by applicant]
Villarino, et al., “Mechanisms of Jak/stat Signaling in Immunity and Disease,” The Journal of Immunology (2015) 194(1):21-27. [cited by applicant]
Von Heijne, Gunnar, ed. Sequence analysis in molecular biology: treasure trove or trivial pursuit. Elsevier, 2012.; TIBS 13, Oct. 1988, 1 page. [cited by applicant]
Vonrhein, et al. “Automated structure solution with autoSHARP.” Macromolecular Crystallography Protocols: vol. 2: Structure Determination (2007): 215-230. [cited by applicant]
Wang et al., “IgG Fc engineering to modulate antibody effector functions,” Protein Cell 2018, 9(1):63-73. [cited by applicant]
Wang, et al., “A Novel IL-23p19/Ebi3 (IL-39) Cytokine Mediates Inflammation in Lupus-like Mice,” European Journal of Immunology (2016) 46:1343-1350. [cited by applicant]
Wang, et al., “Structural Biology of Shared Cytokine Receptors,” Annual Review of Immunology (2009)27:29-60. [cited by applicant]
Wang, et al. “Selection of pd1/pd-l1 x-aptamers.” Biochimie 145 (2018): 125-130. [cited by applicant]
Watford, et al., “Signaling by IL-12 and IL-23 and the Immunoregulatory Roles of STAT4,” Immunological Reviews (2004) 202:139-156. [cited by applicant]
Weiss et al., “Immunotherapy of Cancer by IL-12-based Cytokine Combinations,” Expert Opin Biol Ther. Nov. 2007 ; 7(11): 1705-1721. [cited by applicant]
Wojno, et al., “The Immunobiology of the Interleukin-12 Family: Room for Discovery,” Immunity (2019) 50(4):851-870. [cited by applicant]
Woo, et al. “Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape.” Cancer research 72, No. 4 (2012): 917-927. [cited by applicant]
Wu, et al. “Immunotherapies: the blockade of inhibitory signals.” International journal of biological sciences 8, No. 10 (2012): 1420. [cited by applicant]
Xue, et al. “Next-generation cytokines for cancer immunotherapy,” Antibody Therapeutics, 2021, vol. 4, No. 2 123-133. [cited by applicant]
Yen, et al. “IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6.” The Journal of clinical investigation 116, No. 5 (2006): 1310-1316. [cited by applicant]
Yeste, et al. “IL-21 induces IL-22 production in CD4+ T cells.” Nature communications 5, No. 1 (2014): 1-13. [cited by applicant]
Yodoi, et al. “TCGF (IL 2)-receptor inducing factor (s). I. Regulation of IL 2 receptor on a natural killer-like cell line (YT cells).” Journal of immunology (Baltimore, Md.: 1950) 134, No. 3 (1985): 1623-1630. [cited by applicant]
Yoon, et alNPL. “Charged residues dominate a unique interlocking topography in the heterodimeric cytokine interleukin-12.” The EMBO journal (2000). [cited by applicant]
Yoshimoto, et al. “IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL-18 for IFN-γ production.” The Journal of Immunology 161, No. 7 (1998): 3400-3407. [cited by applicant]
Zhou, et al., IL-6 programs T (H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways., 2007, 8. DOI: https://doi. org/10.1038/ni1488. PMID: https://www. ncbi. nlm. nih.gov/pubmed/… [cited by applicant]
Zhou, Fang. “Molecular mechanisms of IFN-γ to up-regulate MHC class I antigen processing and presentation.” International reviews of immunology 28, No. 3-4 (2009): 239-260. [cited by applicant]
Zhu, et al. “Differentiation of effector CD4 T cell populations.” Annual review of immunology 28, No. 1 (2009): 445-489. [cited by applicant]
Zitvogel, et al. “Cancer immunotherapy of established tumors with IL-12. Effective delivery by genetically engineered fibroblasts.” Journal of immunology (Baltimore, Md.: 1950) 155, No. 3 (1995): 1393-1403. [cited by applicant]
Anderson, et al. “Construction and biological characterization of an interleukin-12 fusion protein (Flexi-12): delivery to acute myeloid leukemic blasts using adeno-associated virus.” Human gene therapy 8, No. 9 (1997):… [cited by applicant]
Ardolino, et al. “Cytokine therapy reverses NK cell anergy in MHC-deficient tumors.” The Journal of clinical investigation 124, No. 11 (2014): 4781-4794. [cited by applicant]
Aste-Amezaga, et al. “Cooperation of natural killer cell stimulatory factor/interleukin-12 with other stimuli in the induction of cytokines and cytotoxic cell-associated molecules in human T and NK cells.” Cellular immu… [cited by applicant]
Atkins, et al. “Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies.” Clinical cancer research: an official journal of the American Association for Cancer Research 3… [cited by applicant]
Atwell, et al. “Stable heterodimers from remodeling the domain interface of a homodimer using a phage display library.” Journal of molecular biology 270, No. 1 (1997): 26-35. [cited by applicant]
Bastian, et al. “The IL-12 cytokine and receptor family in graft-vs.-host disease.” Frontiers in immunology 10 (2019): 988. [cited by applicant]
Bekaii-Saab, et al. “A phase I trial of paclitaxel and trastuzumab in combination with interleukin-12 in patients with HER2/neu-expressing malignancies.” Molecular cancer therapeutics 8, No. 11 (2009): 2983-2991. [cited by applicant]
Belladonna, et al. “Bioengineering heterodimeric cytokines: turning promiscuous proteins into therapeutic agents.” Biotechnology and Genetic Engineering Reviews 29, No. 2 (2013): 149-174. [cited by applicant]
Benson, et al. “Therapeutic targeting of the IL-12/23 pathways: generation and characterization of ustekinumab.” Nature biotechnology 29, No. 7 (2011): 615-624. [cited by applicant]
Bernett, et al. “564 Potency-reduced and extended half-life IL12 heterodimeric Fc-fusions exhibit strong anti-tumor activity with potentially improved therapeutic index compared to native IL12 agents.” (2020). [cited by applicant]
Bloch, et al. “Structural activation of pro-inflammatory human cytokine IL-23 by cognate IL-23 receptor enables recruitment of the shared receptor IL-12Rβ1.” Immunity 48, No. 1 (2018): 45-58. [cited by applicant]
Boulanger, et al. “Convergent mechanisms for recognition of divergent cytokines by the shared signaling receptor gp130.” Molecular cell 12, No. 3 (2003): 577-589. [cited by applicant]
Boulanger, et al. “Hexameric structure and assembly of the interleukin-6/IL-6 α-receptor/gp130 complex.” Science 300, No. 5628 (2003): 2101-2104. [cited by applicant]
Brunda, et al. “Antitumor and antimetastatic activity of interleukin 12 against murine tumors.” The Journal of experimental medicine 178, No. 4 (1993): 1223-1230. [cited by applicant]
Carter, Paul. “Bispecific human IgG by design.” Journal of immunological methods 248, No. 1-2 (2001): 7-15. [cited by applicant]
Chao, et al. “Isolating and engineering human antibodies using yeast surface display.” Nature protocols 1, No. 2 (2006): 755-768. [cited by applicant]
Chappel, et al. “Identification of the Fc gamma receptor class I binding site in human IgG through the use of recombinant IgG1/IgG2 hybrid and point-mutated antibodies.” Proceedings of the National Academy of Sciences 8… [cited by applicant]
Choudhary, et al. “Lysine acetylation targets protein complexes and co-regulates major cellular functions.” Science 325, No. 5942 (2009): 834-840. [cited by applicant]
Chua, et al. “Expression cloning of a human IL-12 receptor component. A new member of the cytokine receptor superfamily with strong homology to gp130.” Journal of immunology (Baltimore, Md.: 1950) 153, No. 1 (1994): 128… [cited by applicant]
Collison, et al. “The inhibitory cytokine IL-35 contributes to regulatory T-cell function.” Nature 450, No. 7169 (2007): 566-569. [cited by applicant]
Cooper et al., “Mice Lacking Bioactive II-12 Can Generate Protective, Antigen-specific Cellular Responses to Mycobacterial Infection Only if the II-12 P40 Subunit is Present.” J Immunol 168 (2002): 1322-1327. [cited by applicant]
Decken, et al. “Interleukin-12 is essential for a protective Th1 response in mice infected with Cryptococcus neoformans.” Infection and immunity 66, No. 10 (1998): 4994-5000. [cited by applicant]
Deiters, et al. “Site-specific PEGylation of proteins containing unnatural amino acids.” Bioorganic & Medicinal Chemistry Letters 14, No. 23 (2004): 5743-5745. [cited by applicant]
Delano, et al. “Convergent solutions to binding at a protein-protein interface.” Science 287, No. 5456 (2000): 1279-1283. [cited by applicant]
Desmyter, et al. “Neutralization of human interleukin 23 by multivalent nanobodies explained by the structure of cytokine-nanobody complex.” Frontiers in Immunology 8 (2017): 884. [cited by applicant]
Dorai, et al. “Role of inter-heavy and light chain disulfide bonds in the effector functions of human immunoglobulin IgG1.” Molecular immunology 29, No. 12 (1992): 1487-1491. [cited by applicant]
Dozier, et al. “Site-specific PEGylation of therapeutic proteins.” International journal of molecular sciences 16, No. 10 (2015): 25831-25864. [cited by applicant]
Economides, et al. “Cytokine traps: multi-component, high-affinity blockers of cytokine action.” Nature medicine 9, No. 1 (2003): 47-52. [cited by applicant]
Fewell, et al. “Treatment of disseminated ovarian cancer using nonviral interleukin-12 gene therapy delivered intraperitoneally.” The Journal of Gene Medicine: A cross-disciplinary journal for research on the science of… [cited by applicant]
Foss, et al. “In Vitro and In Vivo Bioactivity of Single-Chain Interleukin-12.” Scandinavian journal of immunology 50, No. 6 (1999): 596-604. [cited by applicant]
Gafner, et al. “An engineered antibody-interleukin-12 fusion protein with enhanced tumor vascular targeting properties.” International journal of cancer 119, No. 9 (2006): 2205-2212. [cited by applicant]
Georgy, et al. “Tryptophan (W) at position 37 of murine IL-12/IL-23 p40 is mandatory for binding to IL-12Rβ1 and subsequent signal transduction.” Journal of Biological Chemistry 297, No. 5 (2021). [cited by applicant]
Gillies, et al. “Antibody-IL-12 fusion proteins are effective in SCID mouse models of prostate and colon carcinoma metastases.” The Journal of Immunology 160, No. 12 (1998): 6195-6203. [cited by applicant]
Gillies, wt al. “Bi-functional cytokine fusion proteins for gene therapy and antibody-targeted treatment of cancer.” Cancer Immunology, Immunotherapy 51 (2002): 449-460. [cited by applicant]
Glassman, et al. “Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells.” Manuscript No. Cell-D-20-00989R5, 85 pages. [cited by applicant]
Ha, et al. “Immunoglobulin Fc heterodimer platform technology: from design to applications in therapeutic antibodies and proteins.” Frontiers in Immunology 7 (2016): 394. [cited by applicant]
Jiang, et al. “Sustained expression of Fc-fusion cytokine following in vivo electroporation and mouse strain differences in expression levels.” Journal of biochemistry 133, No. 4 (2003): 423-427. [cited by applicant]
Jung, et al. “Heterodimeric Fc-fused IL12 shows potent antitumor activity by generating memory CD8+ T cells.” Oncoimmunology 7, No. 7 (2018): e1438800. [cited by applicant]
Kobayashi, et al. “Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes.” The Journal of experimental medicine 170, No. 3 (1989… [cited by applicant]
Kontermann, Roland E. “Half-life extended biotherapeutics.” Expert opinion on biological therapy 16, No. 7 (2016): 903-915. [cited by applicant]
Kopp, et al. “Clinical improvement in psoriasis with specific targeting of interleukin-23.” Nature 521, No. 7551 (2015): 222-226. [cited by applicant]
Koutruba et al., Review of Ustekinumab, an Interleukin-12 and Interleukin-23 Inhibitor Used for the Treatment Of Plaque Psoriasis, Therapeutics and Clinical Risk Management, Mar. 8, 2010, 6:123-141. [cited by applicant]
Lasek, et al. “Interleukin 12: still a promising candidate for tumor immunotherapy?.” Cancer Immunology, Immunotherapy 63 (2014): 419-435. [cited by applicant]
Leong, et al. “Optimized expression and specific activity of IL-12 by directed molecular evolution.” Proceedings of the National Academy of Sciences 100, No. 3 (2003): 1163-1168. [cited by applicant]
Liang, et al. “IL-23 receptor expression on γδ T cells correlates with their enhancing or suppressive effects on autoreactive T cells in experimental autoimmune uveitis.” The Journal of Immunology 191, No. 3 (2013): 111… [cited by applicant]
Littman, et al. “Th17 and regulatory T cells in mediating and restraining inflammation.” Cell 140, No. 6 (2010): 845-858. [cited by applicant]
Lo, et al. “Effector-attenuating substitutions that maintain antibody stability and reduce toxicity in mice.” Journal of Biological Chemistry 292, No. 9 (2017): 3900-3908. [cited by applicant]
Low, et al. “Oral and pulmonary delivery of FSH-Fc fusion proteins via neonatal Fc receptor-mediated transcytosis.” Human reproduction 20, No. 7 (2005): 1805-1813. [cited by applicant]
Luo, et al. “Structural basis for the dual recognition of IL-12 and IL-23 by ustekinumab.” Journal of molecular biology 402, No. 5 (2010): 797-812. [cited by applicant]
Lupardus, et al. “The structure of interleukin-23 reveals the molecular basis of p40 subunit sharing with interleukin-12.” Journal of molecular biology 382, No. 4 (2008): 931-941. [cited by applicant]
Mattner, et al. “Genetically resistant mice lacking interleukin-12 are susceptible to infection with Leishmania major and mount a polarized Th2 cell response.” European journal of immunology 26, No. 7 (1996): 1553-1559. [cited by applicant]
Merchant, et al. “An efficient route to human bispecific IgG.” Nature biotechnology 16, No. 7 (1998): 677-681. [cited by applicant]
Murray, Peter J. “The JAK-STAT signaling pathway: input and output integration.” The Journal of Immunology 178, No. 5 (2007): 2623-2629. [cited by applicant]
Nguyen, et al. “Localized interleukin-12 for cancer immunotherapy.” Frontiers in immunology 11 (2020): 575597. [cited by applicant]
Oppmann, et al. “Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12.” Immunity 13, No. 5 (2000): 715-725. [cited by applicant]
Parham, et al. “A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R.” The Journal of Immunology 168, No. 11 (2002): 5699-5708. [cited by applicant]
Pasche, et al. “The antibody-based delivery of interleukin-12 to the tumor neovasculature eradicates murine models of cancer in combination with paclitaxel.” Clinical Cancer Research 18, No. 15 (2012): 4092-4103. [cited by applicant]
Pegram, et al. “Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning.” Blood, The Journal of the American Society of Hematology 119, No. 18 (2012): 4133-4141. [cited by applicant]
Peng, et al. “A single-chain IL-12 IgG3 antibody fusion protein retains antibody specificity and IL-12 bioactivity and demonstrates antitumor activity.” The Journal of Immunology 163, No. 1 (1999): 250-258. [cited by applicant]
Presky, et al. “A functional interleukin 12 receptor complex is composed of two β-type cytokine receptor subunits.” Proceedings of the National Academy of Sciences 93, No. 24 (1996): 14002-14007. [cited by applicant]
Rath, et al. “Fc-fusion proteins and FcRn: structural insights for longer-lasting and more effective therapeutics.” Critical reviews in biotechnology 35, No. 2 (2015): 235-254. [cited by applicant]
Ridgway, et al. “'Knobs-into-holes' engineering of antibody CH3 domains for heavy chain heterodimerization.” Protein Engineering, Design and Selection 9, No. 7 (1996): 617-621. [cited by applicant]
Scallon, et al. “Quantitative in vivo comparisons of the Fcγ receptor-dependent agonist activities of different fucosylation variants of an immunoglobulin G antibody.” International immunopharmacology 7, No. 6 (2007): 7… [cited by applicant]
Schlothauer, et al. “Novel human IgG1 and IgG4 Fc-engineered antibodies with completely abolished immune effector functions.” Protein Engineering, Design and Selection 29, No. 10 (2016): 457-466. [cited by applicant]
Schmidt, Stefan R. “Fusion-proteins as biopharmaceuticals-applications and challenges.” Curr Opin Drug Discov Devel 12, No. 2 (2009): 284-295. [cited by applicant]
Schröder, et al. “Non-canonical interleukin 23 receptor complex assembly: p40 protein recruits interleukin 12 receptor β1 via site II and induces p19/interleukin 23 receptor interaction via site III.” Journal of Biologi… [cited by applicant]
Schurich, et al. “The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells.” PLoS pathogens 9, No. 3 (2013): e1003208. [cited by applicant]
Skiniotis, et al. “Structural organization of a full-length gp130/LIF-R cytokine receptor transmembrane complex.” Molecular cell 31, No. 5 (2008): 737-748. [cited by applicant]
Skrombolas, et al. “Characterization of an IL-12 p40/p35 truncated fusion protein that can inhibit the action of IL-12.” Journal of Interferon & Cytokine Research 35, No. 9 (2015): 690-697. [cited by applicant]
Skrombolas, et al. “Development of an interleukin-12 fusion protein that is activated by cleavage with matrix metalloproteinase 9.” Journal of Interferon & Cytokine Research 39, No. 4 (2019): 233-245. [cited by applicant]
Strohl, William R. “Optimization of Fc-mediated effector functions of monoclonal antibodies.” Current opinion in biotechnology 20, No. 6 (2009): 685-691. [cited by applicant]
Tamura, et al. “Intratumoral delivery of interleukin 12 expression plasmids with in vivo electroporation is effective for colon and renal cancer.” Human gene therapy 12, No. 10 (2001): 1265-1276. [cited by applicant]
Trinchieri, Giorgio. “Interleukin-12 and the regulation of innate resistance and adaptive immunity.” Nature Reviews Immunology 3, No. 2 (2003): 133-146. [cited by applicant]
Tugues, et al. “New insights into IL-12-mediated tumor suppression.” Cell Death & Differentiation 22, No. 2 (2015): 237-246. [cited by applicant]
Valeich, et al. “Taking the Hinge off: An Approach to Effector-Less Monoclonal Antibodies.” Antibodies 9, No. 4 (2020): 50. [cited by applicant]
Vazquez-Lombardi, et al. “Molecular engineering of therapeutic cytokines.” Antibodies 2, No. 3 (2013): 426-451. [cited by applicant]
Vignali, et al. “IL-12 family cytokines: immunological playmakers.” Nature immunology 13, No. 8 (2012): 722-728. [cited by applicant]
Villarino, et al. “Mechanisms of Jak/STAT signaling in immunity and disease.” The Journal of Immunology 194, No. 1 (2015): 21-27. [cited by applicant]
Wang, et al. “A novel IL-23p19/Ebi3 (IL-39) cytokine mediates inflammation in Lupus-like mice.” European journal of immunology 46, No. 6 (2016): 1343-1350. [cited by applicant]
Wang, et al. “Structural biology of shared cytokine receptors.” Annual review of immunology 27 (2009): 29-60. [cited by applicant]
Watford, et al. “Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4.” Immunological reviews 202, No. 1 (2004): 139-156. [cited by applicant]
Weiss, et al. “Immunotherapy of cancer by IL-12-based cytokine combinations.” Expert opinion on biological therapy 7, No. 11 (2007): 1705-1721. [cited by applicant]
Wojino, et al. “The immunobiology of the interleukin-12 family: room for discovery.” Immunity 50, No. 4 (2019): 851-870. [cited by applicant]
Xue, et al. “Next-generation cytokines for cancer immunotherapy.” Antibody Therapeutics 4, No. 2 (2021): 123-133. [cited by applicant]
Yoon, et al. “Charged residues dominate a unique interlocking topography in the heterodimeric cytokine interleukin-12.” The EMBO journal 19, No. 14 (2000): 3530-3541. [cited by applicant]
Zhang, et al. “Improving adoptive T cell therapy by targeting and controlling IL-12 expression to the tumor environment.” Molecular therapy 19, No. 4 (2011): 751-759. [cited by applicant]
Zhou, et al. “IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways.” Nature immunology 8, No. 9 (2007): 967-974. [cited by applicant]
Application No. EP 21788055.8, Extended European Search Report, dated May 6, 2024, 9 pages. [cited by applicant]
Belladonna et al., “IL-12 Have Overlapping, but Distinct, Effects on Murine Dendritic Cells”, The Journal of Immunology, vol. 168, No. 11, Jun. 1, 2002, pp. 5448-5454. [cited by applicant]
Rudman et al.,“A phase 1 study of AS1409, a novel antibody-cytokine fusion protein, in patients with malignant melanoma or renal cell carcinoma,” Clin Cancer Res., 17(7): Apr. 1, 2011, pp. 1998-2005. [cited by applicant]
Application No. EP 22884703.4, Extended European Search Report, Mailed On Sep. 24, 2025, 12 pages. [cited by applicant]