Encapsulated cells expressing IL-12 and uses thereof
The present disclosure relates to implantable constructs (encapsulated cells) designed to deliver therapeutic reagents, such as IL-12 and/or IL-12 and methods of using the same to treat conditions, such as cancer.
1 . A population of encapsulated cells comprising a plurality of oligonucleotide molecules encoding a IL-12 polypeptide, wherein the native human IL-12 polypeptide is a heterodimeric complex comprising a native human IL-12 (p35) polypeptide and a native human IL-12 (p40) polypeptide, further wherein the IL-12 (p35) polypeptide and the IL-12 (p40) polypeptide is expressed at a ratio (IL-12 (p35):IL-12 (p40)) of about 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.
2 . The population of encapsulated cells of claim 1 , wherein the IL-12 polypeptide is a native human IL-12 polypeptide, a recombinant IL-12 polypeptide, or a IL-12 mutein polypeptide.
3 . The population of encapsulated cells of claim 2 , wherein the recombinant IL-12 is a heterodimeric complex comprising a recombinant IL-12 (p35) polypeptide and a recombinant IL-12 (p40) polypeptide.
4 . The population of encapsulated cells of claim 2 , wherein the IL-12 mutein is a heterodimeric complex comprising an IL-12 (p35) mutein polypeptide and an IL-12 (p40) mutein polypeptide.
5 . The population of encapsulated cells of claim 4 , wherein the IL-12 (p40) mutein polypeptide comprises a mutation selected from N220L, N222L or N222Q as compared to the amino acid sequence of SEQ ID NO: 4.
6 . The population of encapsulated cells of claim 1 , wherein the plurality of oligonucleotide molecules encodes the native human IL-12 (p35) polypeptide and the native human IL-12 (p40) polypeptide.
7 . The population of encapsulated cells claim 1 , wherein the oligonucleotide encoding the native human IL-12 (p35) polypeptide comprises a sequence of SEQ ID NO: 1 and the oligonucleotide encoding the native human IL-12 (p40) polypeptide comprises a sequence of SEQ ID NO: 2.
8 . The population of encapsulated cells of any one of claim 1 , wherein the expressed IL-12 (p35) polypeptide and the expressed IL-12 (p40) polypeptide form a heterodimeric complex.
9 . The population of encapsulated cells of claim 1 , wherein the population of cells produces about 10 to about 50, about 10 to about 30, about 10 to about 20, or about 20 nanograms/cell/day of native human IL-12.
10 . The population of encapsulated cells of claim 1 , wherein the cells are ARPE-19 cells, ARPE-19-SEAP-2-neo cells, RPE-J cells, hTERT RPE-1 cells, or any combination thereof.
11 . The population of encapsulated cells of claim 1 , wherein the cells are encapsulated with a polymeric hydrogel.
12 . The population of encapsulated cells claim 11 , wherein the polymeric hydrogel comprises chitosan, cellulose, hyaluronic acid, or alginate.
13 . The population of encapsulated cells of claim 11 , wherein the cells remain viable for at least 5, 10, 15, 20, 40, 120, or 180 days.
14 . The population of encapsulated cells of claim 1 , wherein the encapsulated cells do not proliferate.
15 . The population of encapsulated cells of claim 1 , wherein the capsule encapsulating the population of cells does not develop fibrotic overgrowth or develops partial fibrotic overgrowth after implantation in a subject.
16 . A pharmaceutical composition comprising the population of encapsulated cells of claim 1 .
17 . The pharmaceutical composition of claim 16 , further comprising a population of encapsulated cells comprising an oligonucleotide molecule encoding native human IL-2.
18 . A method of:
treating a tumor or cancer, in a subject, the method comprising implanting in the intraperitoneal space of the subject a pharmaceutical composition comprising a plurality of encapsulated cells of claim 1 to treat the tumor or the cancer in the subject;
reducing tumor burden, in a subject, the method comprising implanting in the intraperitoneal space of the subject a pharmaceutical composition comprising a plurality of encapsulated cells of claim 1 to the subject to reduce the tumor burden in the subject;
treating a tumor, or reducing tumor burden, in a subject by generating memory immunity, the method comprising implanting in, or administering to, the subject a pharmaceutical composition comprising the population of encapsulated cells of claim 1 in the subject;
selectively activating CD8 positive effector T cells in a subject, the method comprising implanting in, or administering to, the subject a pharmaceutical composition comprising a population of encapsulated cells of claim 1 in the subject;
increasing interferon gamma (IFN-γ) in a subject, the method comprising implanting in, or administering to, the subject pharmaceutical composition comprising a population of encapsulated cells of claim 1 in the subject;
preventing or inhibiting fibrosis of a capsule encapsulating cells implanted in a subject, the method comprising having the implanted encapsulated cells express IL-12 or exposing the implanted encapsulated cells to IL-12 at the location of implantation.