Implantable constructs and uses thereof
The present disclosure relates to implantable constructs designed to deliver antigenic therapeutic reagents to a subject while providing protection from host immune responses. In certain aspects, the constructs are designed to degrade over time or upon a particular signal, thereby providing control of the length of time the therapeutic agent is delivered to the subject.
1 . An implantable construct comprising:
(i) an inner alginate layer encapsulating a a plurality of retinal epithelial pigment cells expressing human IL-2,
(ii) an outer alginate layer,
wherein the implantable construct:
is configured for implantation into the intraperitoneal space or the pleural cavity of a subject, and
is further configured to provide a first release phase wherein the rate of release of the human IL-2 is substantially constant and a second release phase wherein the level of release of the human IL-2 is substantially declining.
2 . The implantable construct of claim 1 , wherein the plurality of retinal epithelial pigment cells are ARPE-19 cells.
3 . The implantable construct of claim 1 , wherein the plurality of retinal epithelial pigment comprises greater than about 1000 cells expressing IL-2.
4 . The intraperitoneal space implantable construct of claim 1 , wherein the plurality of retinal epithelial pigment comprises greater than about 1000 cells expressing IL-2 and less than 1×10 5 expressing IL-2 cells.
5 . The implantable construct of claim 1 , wherein the implantable construct secretes IL-2 for about 4 weeks when implanted in a subject.
6 . The implantable construct of claim 1 , wherein the implantable construct has a decrease in function about 2 weeks after implantation in the subject.
7 . The intraperitoneal space implantable construct of claim 6 , wherein the decrease in function is a decrease in secretion of the IL-2.
8 . The implantable construct of claim 1 , wherein the implantable construct becomes fibrosed after implantation in a subject.
9 . The implantable construct of claim 1 , wherein the implantable construct does not comprise an antifibrotic feature.
10 . A method of treating cancer or reducing tumor size in a subject, the method comprising implanting into the intraperitoneal space or the pleural cavity of a subject the implantable construct of claim 1 .
11 . The method of claim 10 , wherein the concentration of the secreted IL-2 in the intraperitoneal space of the subject is 2-fold or more than the concentration of the secreted IL-2 in the blood of the subject when the implantable construct is implanted in the intraperitoneal space.
12 . The method of claim 10 , wherein the concentration of the secreted IL-2 in the intraperitoneal space of the subject is 50-fold or more than the concentration of the secreted IL-2 in the blood of the subject when the implantable construct is implanted in the intraperitoneal space.
13 . The method of claim 10 , wherein the concentration of the secreted IL-2 in the intraperitoneal space of the subject is 50-fold or more than the concentration of the secreted IL-2 in the blood of the subject for at least 6 days after implantation in the intraperitoneal space.
14 . The method of claim 10 , wherein the implantable construct does not comprise an antifibrotic feature.
15 . The implantable construct of claim 1 , wherein the implantable construct is coated with fibrotic overgrowth after being implanted in the subject.
16 . The implantable construct of claim 1 , wherein fibrotic overgrowth causes a decrease in function of the implantable construct about 2 weeks after implantation in the subject.
17 . The method of claim 10 , wherein the cancer is pancreatic cancer or melanoma, or the tumor is a pancreatic tumor or melanoma.
18 . The method of claim 10 , wherein the concentration of the secreted IL-2 in the intraperitoneal space decreases between 2 and 4 weeks after implantation in the intraperitoneal space.
19 . The method of claim 10 , wherein the implantation of the implantable construct produces an upregulation in T effector cells.
20 . The method of claim 19 , wherein the implantation does not activate a T regulator cell in the subject.
21 . The implantable construct of claim 1 , wherein the implantable construct has a mean diameter size of 1 mm or larger.
22 . The implantable construct of claim 1 , and wherein the implantable construct comprises a sphere.