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WO 2018/102612 Al 07 June 2018 (07.06.2018) W !P O PCT

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WO 2018/102612 Al 07 June 2018 (07.06.2018) W !P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/102612 Al 07 June 2018 (07.06.2018) W !P O PCT (51) International Patent Classification: Published: CI2N 15/66 (2006.01) — with international search report (Art. 21(3)) (21) International Application Number: — before the expiration of the time limit for amending the PCT/US20 17/064075 claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) (22) International Filing Date: — with sequence listing part of description (Rule 5.2(a)) 30 November 20 17 (30. 11.201 7) (25) Filing Language: English (26) Publication Langi English (30) Priority Data: 62/429,709 02 December 20 16 (02.12.20 16) US (71) Applicant: JUNO THERAPEUTICS, INC. [US/US]; 400 Dexter Ave. North, Suite 1200, Seattle, WA 98109 (US). (72) Inventor: LEVITSKY, Hyam I.; 400 Dexter Ave. North, Suite 1200, Seattle, WA 98109 (US). (74) Agent: AIKEN, Charity et al; Morrison & Foerster LLP, 12531 High Bluff Drive, Suite 100, San Diego, CA 92130-2040 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Declarations under Rule 4.17: — as to the applicant's entitlement to claim the priority of the earlier application (Rule 4.1 7(in)) (54) Title: ENGINEERED B CELLS AND RELATED COMPOSITIONS AND METHODS o (57) Abstract: Provided herein are engineered B cells, such as for adoptive cell therapy. In some aspects, also provided are methods and compositions for engineering and producing the cells, compositions containing the cells, and methods for their administration to 00 subjects. In some embodiments, the cells are engineered to produce and/or secrete an exogenous protein, such as a therapeutic protein, o including antibodies and antigen-binding fragments thereof. In some aspects, features of the cells and methods provide for increased or improved activity, efficacy and/or persistence of the cells. o ENGINEERED B CELLS AND RELATED COMPOSITIONS AND METHODS Cross-Reference to Related Applications [0001] This application claims priority from U.S. provisional application No. 62/429,709 filed December 2, 2016, entitled "Engineered B Cells and Related Compositions and Methods," the contents of which are incorporated by reference in their entirety. Incorporation by Reference of Sequence Listing [0002] The present application is being filed with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 735042006640seqlist.txt, created November 30, 2017, which is 64,032 bytes in size. The information in electronic format of the Sequence Listing is incorporated by reference in its entirety. Field [0003] The present disclosure relates in some aspects to engineered B cells, such as for adoptive cell therapy. In some aspects, the disclosure further relates to methods and compositions for engineering and producing the cells, compositions containing the cells, and methods for their administration to subjects. In some embodiments, the cells are engineered to produce and/or secrete an exogenous protein, such as a therapeutic protein, including antibodies and antigen-binding fragments thereof. In some aspects, features of the cells and methods provide for increased or improved activity, efficacy and/or persistence of the cells. Background [0004] Various methods are available for treating diseases, including infectious diseases, cancers, and autoimmune diseases, using therapeutic proteins, such as antibodies or antigen- binding fragments thereof. Such approaches generally involve repeated injections of recombinantly-produced proteins, which can provide various therapeutic effects via one or more mechanisms. The presence of the therapeutic proteins in the body following administration is generally transient. Improved compositions and methods are needed, for example, to improve efficacy of such therapies, for example, by increasing the duration of action of the therapies. Provided are products, compositions, methods and articles of manufacture that meet such needs. Summary [0005] Provided are engineered B cells capable of producing and/or secreting an exogenous protein, such as a therapeutic protein, such as for use in adoptive cell therapy, for example to treat diseases and/or conditions in a subject in need thereof. Also provided are compositions comprising the cells, methods of producing and using the cells, such as for treating a disease and/or condition, and articles of manufacture comprising the cells or for use in a method described herein. [0006] In some embodiments, provided are engineered B cells comprising one or more nucleic acid molecules comprising one or more coding sequences encoding an exogenous protein under the control of one or more elements to effect secretion of the exogenous protein from the cell, wherein the exogenous protein is not an antibody. [0007] In some embodiments, provided are engineered B cells comprising one or more nucleic acid molecules comprising one or more coding sequences encoding an exogenous protein, wherein expression of the exogenous protein in the engineered B cell is conditional. [0008] In some embodiments, provided are engineered B cells comprising one or more nucleic acid molecules comprising one or more coding sequences encoding an exogenous protein, wherein the engineered B cell expresses an endogenous antibody and comprises a modification that prevents class-switching of the endogenous antibody and/or prevents switching of the endogenous antibody from a membrane-associated form to a secreted form. [0009] In some embodiments, provided are engineered B cells comprising one or more nucleic acid molecules comprising one or more coding sequences encoding an exogenous protein, wherein at least one of the one or more nucleic acid molecules is integrated into or replaces all or a portion of a heavy chain immunoglobulin locus or a light chain immunoglobulin locus of the B cell. [0010] In some embodiments, provided are engineered B cells comprising one or more nucleic acid molecules comprising one or more coding sequences encoding an exogenous protein, wherein the engineered B cell comprises one or more modifications resulting in a greater capacity for the engineered B cell to produce and/or secrete the exogenous protein. [0011] In some embodiments, provided are engineered B cells comprising: one or more nucleic acid molecules comprising one or more coding sequences encoding an exogenous protein; and a chimeric receptor comprising a ligand binding domain, wherein, upon ligand binding, the receptor is capable of inducing (i) a mitogenic or proliferative signal; and/or (ii) a signal that is capable of modulating the differentiation of the engineered B cell. [0012] In some embodiments, provided are engineered B cells comprising: one or more nucleic acid molecules comprising one or more coding sequences encoding an exogenous protein; and a recombinant receptor comprising a ligand binding domain, wherein, upon ligand binding, the receptor is capable of inducing (i) a mitogenic or proliferative signal; and/or (ii) a signal that is capable of modulating the differentiation of the engineered B cell, wherein the exogenous protein does not bind to the target of the ligand binding domain of the receptor and/or the exogenous protein does not contain a ligand binding site contained in the ligand binding domain of the receptor. [0013] In some of any such embodiments, the exogenous protein is secreted by the B cell or is capable of being secreted by the B cell. In some embodiments, the one or more coding sequences comprises a nucleotide sequence encoding a secretory signal peptide. In some embodiments, the secretory signal peptide comprises an amino acid sequence selected from among SEQ ID NOs: 76-202. [0014] In some of any such embodiments, the exogenous protein is a dimer. In some embodiments, the one or more nucleic acid molecules comprises a single nucleic acid molecule comprising a first coding sequence encoding a first domain or subunit of the dimer and a second coding sequence encoding a second domain or subunit of the dimer. [0015] In some of any such embodiments, the exogenous protein is a therapeutic protein. [0016] In some of any such embodiments, the exogenous protein binds to a target molecule associated with a disease or condition, wherein the molecule is optionally a protein, wherein the molecule or protein is expressed on the surface of a cell. In some embodiments, the disease or condition is selected from among a tumor or cancer, an autoimmune disease, an infectious disease or condition, and an inflammatory disease. In some embodiments, the disease or condition is a tumor or cancer. In some embodiments, the disease or condition is a viral infection.
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