Trophoblast glycoprotein (5T4, TPBG) specific chimeric antigen receptors for cancer immunotherapy
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Publication Number
US-11987639-B2
Publication Date
2024-05-21
Expiration Date
Abstract
The present invention relates to Chimeric Antigen Receptors (CAR) that are recombinant chimeric proteins able to redirect immune cell specificity and reactivity toward selected membrane antigens, and more particularly in which extracellular ligand binding is a scFV derived from a 5T4 monoclonal antibody, conferring specific immunity against 5T4 positive cells. The engineered immune cells endowed with such CARs are particularly suited for treating lymphomas and leukemia, and for solid tumors such as colon, stomach, and ovarian tumors.
Core Innovation
The patent describes polynucleotides encoding a 5T4 (NTRKR1) specific chimeric antigen receptor (CAR) and engineered immune cells expressing the same. The CAR includes an extracellular ligand binding-domain comprising a variable heavy chain, a variable light chain, a CD8α hinge, and a CD8α transmembrane domain, and a cytoplasmic domain comprising a CD3 zeta signaling domain and a co-stimulatory domain from 4-1BB.
The ligand binding-domain is defined by specifying CDR regions for the variable heavy chain and the variable light chain using SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53. The engineered immune cell embodiments further define sequence-identity constraints for the hinge, transmembrane domain, signaling domain, and co-stimulatory domain relative to corresponding SEQ ID sequences.
Claims Coverage
The provided claim set includes three independent claims. Across these claims, the core CAR architecture is defined by extracellular variable heavy and variable light chains with specified CDR regions, a CD8α hinge and CD8α transmembrane domain, and a cytoplasmic CD3 zeta signaling domain together with a 4-1BB co-stimulatory domain, with one claim adding explicit sequence-identity thresholds and another adding expression on the cell surface.
5T4-specific CAR polynucleotide with specified CDR regions and CD8α/4-1BB signaling architecture
A polynucleotide encoding a 5T4 (NTRKR1) specific chimeric antigen receptor (CAR) comprising an extracellular ligand binding-domain comprising a variable heavy chain, a variable light chain, a CD8α hinge, and a CD8α transmembrane domain and a cytoplasmic domain comprising a CD3 zeta signaling domain and a co-stimulatory domain from 4-1BB, wherein the variable heavy chain comprises CDR regions as set forth in SEQ ID NO:48, SEQ ID NO:49, and SEQ ID NO:50, and wherein the variable light chain comprises CDR regions as set forth in SEQ ID NO:51, SEQ ID NO:52, and SEQ ID NO:53.
Engineered immune cell expressing a 5T4-specific CAR on the cell surface with CD8α/4-1BB signaling architecture
An engineered immune cell expressing a 5T4 (NTRKR1) specific chimeric antigen receptor (CAR) comprising an extracellular ligand binding-domain comprising a variable heavy chain, a variable light chain, a CD8α hinge, and a CD8α transmembrane domain and a cytoplasmic domain comprising a CD3 zeta signaling domain and a co-stimulatory domain from 4-1BB, wherein the 5T4 specific CAR is expressed on a cell surface membrane of the immune cell, wherein the variable heavy chain comprises CDR regions as set forth in SEQ ID NO:48, SEQ ID NO:49, and SEQ ID NO:50, and wherein the variable light chain comprises CDR regions as set forth in SEQ ID NO:51, SEQ ID NO:52, and SEQ ID NO:53.
5T4-specific CAR with sequence-identity constrained hinge, transmembrane, signaling, and co-stimulatory domains
An engineered immune cell expressing a 5T4 (NTRKR1) specific chimeric antigen receptor (CAR) having an extracellular ligand binding-domain with a variable heavy chain comprising CDR regions as set forth in SEQ ID NO:48, SEQ ID NO:49, and SEQ ID NO:50 and a variable light chain comprising CDR regions as set forth in SEQ ID NO:51, SEQ ID NO:52, and SEQ ID NO:53; a hinge comprising an amino acid sequence at least 95 percent identical to SEQ ID NO:4; a transmembrane domain comprising an amino acid sequence at least 95 percent identical to SEQ ID NO:6; and a cytoplasmic domain comprising a signaling domain comprising an amino acid sequence at least 95 percent identical to SEQ ID NO:9 and a co-stimulatory domain comprising an amino acid sequence at least 95 percent identical to SEQ ID NO:8, wherein the 5T4 specific CAR is expressed on the cell surface membrane.
Collectively, the independent claims cover a 5T4 (NTRKR1) specific CAR defined by specified CDR regions for variable heavy and variable light chains and by a CD8α hinge/CD8α transmembrane extracellular structure paired with a cytoplasmic CD3 zeta signaling domain and 4-1BB co-stimulatory domain, with one claim emphasizing surface expression in an engineered immune cell and another further constraining hinge, transmembrane, signaling, and co-stimulatory domains by at least 95 percent sequence identity to referenced SEQ ID sequences.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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