Conditionally active heterodimeric polypeptides and methods of use thereof
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example 1
ed on-Switch Car Constructs
[0866]PPARγ-based ON-switch CAR constructs were generated. FIG. 12 presents a schematic diagram of the overall structure of a generalized nuclear hormone ligand binding domain (LBD) / co-activator peptide ON-switch CAR. FIG. 13 presents a schematic diagram of the overall structure of the constructs. Constructs are listed in Table 3. ON-switch constructs (bCW197, bCW206, bCW207), with FKBP and FRB* domains, were used as positive and negative control CARs.
TABLE 3construct ID #encoded CAR moleculebCW492Part 1 (antigen binding) with SRC3co-regulator peptide, short versionbCW493Part 1 with SRC3 co-regulator peptide,short version, 3 tandem copiesbCW494Part 1 with SRC3 co-regulator peptide,long versionbCW495Part 2 with PPARgamma LBD
[0867]Amino acid sequences of the ligand-binding domain (LBD) of PPARγ included in the CAR constructs, and amino acid sequences of the co-regulator peptides used, are set forth below.
[0868]The amino acid sequence of the LBD of PPARγ incl...
example 2
Based on-Switch Car Constructs
[0880]ERα-based ON-switch CAR constructs were generated. FIG. 15 presents a schematic diagram of the overall structure of the constructs. Constructs are listed in Table 4. ON-switch constructs (bCW197, bCW206, bCW207), with FKBP and FRB* domains, were used as positive and negative control CARs.
TABLE 4construct ID #encoded CAR moleculebCW501Part 1 myc aCD19 ON-switch part 1with 3x AlphaBetaV peptide and 4-1BBbCW502Part 1 myc aCD19 ON-switch part 1with 3x CoRNR peptide and 4-1BBbCW503ON-switch CAR part 2 with human ERalpha LBDbCW504ON-switch CAR part 2 with human ERalpha LBD w Y537FbCW505ON-switch CAR part 2 with human ERalpha LBD w Y537F G521R
[0881]Amino acid sequences of the various components of the ERα-based ON-switch CAR are as follows.
[0882]a. The LBD of human estrogen receptor alpha in construct bCW503:
(SEQ ID NO: 703)DRRGGRMLKHKRQRDDGEGRGEVGSAGDMRAANLWPSPLMIKRSKKNSLALSLTADQMVSALLDAEPPILYSEYDPTRPFSEASMMGLLTNLADRELVHMINWAKRVPGFVDLTLHDQVHLLECAWLEILMI...
example 3
Controlled Activation of Primary Human T Cells
[0915]Control of cellular functions by induced heterodimerization of the ligand binding domain of human estrogen receptor beta with small peptides derived from transcriptional co-repressors in the presence of the drug 4-hydroxytamoxifen was evaluated. This method does not involve DNA-binding and / or transcriptional activation or any DNA-binding function or transcription activating function of the human estrogen receptor beta from which polypeptide components are derived.
[0916]A human estrogen receptor beta nuclear receptor-peptide system was expressed in primary human T cells and found to capable of modulating ON-switch CAR activity. A CD19 specific ON-switch CAR was constructed to include human estrogen receptor beta ligand binding domain and co-repressor peptide (CoRNR). A schematic representation of the general construct within the T cell membrane, and the associated CD19 antigen expressed on the surface of the target cell, is provided...
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