US 11,851,466 B2
Targeted IL-12 heterodimeric Fc-fusion proteins
Matthew Bernett, Monrovia, CA (US); John R. Desjarlais, Pasadena, CA (US); Rajat Varma, Hamden, CT (US); Ke Liu, Glendora, CA (US); Rumana Rashid, Temple City, CA (US); Nargess Hassanzadeh-Kiabi, Pasadena, CA (US); and Michael Hedvat, Encino, CA (US)
Assigned to Xencor, Inc., Pasadena, CA (US)
Filed by Xencor, Inc., Pasadena, CA (US)
Filed on Oct. 2, 2020, as Appl. No. 17/062,458.
Claims priority of provisional application 63/005,100, filed on Apr. 3, 2020.
Claims priority of provisional application 62/910,328, filed on Oct. 3, 2019.
Prior Publication US 2021/0355185 A1, Nov. 18, 2021
Int. Cl. C07K 16/46 (2006.01); C07K 14/54 (2006.01); A61P 35/00 (2006.01); C07K 16/28 (2006.01); A61K 39/00 (2006.01)
CPC C07K 14/5434 (2013.01) [A61P 35/00 (2018.01); C07K 16/2818 (2013.01); C07K 16/2827 (2013.01); A61K 2039/505 (2013.01); C07K 2317/622 (2013.01); C07K 2319/30 (2013.01)] 16 Claims
OG exemplary drawing
 
1. A targeted IL-12 heterodimeric Fc fusion protein comprising:
a) a first monomer comprising, from N- to C-terminal:
i) a first IL-12 protein domain;
ii) a first domain linker;
iii) a second IL-12 protein domain;
iv) a second domain linker; and
v) a first variant human IgG Fc domain comprising CH2-CH3; and
b) second monomer comprising, from N- to C-terminal:
i) an scFv domain;
ii) a third domain linker; and
iii) a second variant human IgG Fc domain comprising CH2-CH3;
wherein either said first IL-12 protein domain comprises an 1L-12p35 subunit and said second IL-12 protein domain comprises an 1L-12p40 subunit, or said first IL-12 protein domain comprises an 1L-12p40 subunit and said second IL-12 protein domain comprises an 1L-12p35 subunit,
wherein said first monomer binds a dimeric IL-12 receptor complex,
wherein said scFv domain comprises a variable heavy domain, an scFv linker, a variable light domain, and said scFv domain binds a target antigen, and
wherein said first and said second variant human IgG Fc domains comprise modifications promoting heterodimerization of said first and said second variant human IgG Fe domains, and
wherein said 1L-12p40 subunit is a variant 1L-12p40 subunit, and
wherein said variant 1L-12p40 subunit comprises an amino acid sequence that differs from that of SEQ ID NO:4 by virtue of an amino acid substitution at one or more amino acid residues selected from the group consisting of E59, K99, D18, K264, C252, N200, E3, D7, E12, D14, W15, P17, A19, P20, G21, E22, M23, D29, E32, E33, D34, L40, D41, Q42, S43, E45, L47, T54, 155, Q56, K58, F60, G61, D62, Q65, Y66, E73, K84, E86, D87, G88, 189, W90, D93, D97, E100, K102, N103, K104, F106, E110, N113, Y114, D129, D142, Q144, E156, R159, D161, N162, K163, D166, D170, Q172, D174, A176, C177, P178, A179, A180, E181, 5183, P185, E187, S204, F206, R208, D209, D214, N218, Q220, N226, Q229, E231, E235, T242, P243, S245, Y246, F247, S248, Q256, K258, K260, E262, D265, D270, N281, 0289, D290, R291, Y292, Y293, and E299.