CD6 targeted chimeric antigen receptors for treatment of certain autoimmune disorders
Inventors
Casemiro, Jose Enrique Montero • Roep, Bart Otto • Brown, Christine E.
Assignees
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Publication Number
US-12281151-B2
Publication Date
2025-04-22
Expiration Date
Abstract
Provided herein are, inter alia, CD6 targeting CAR-T cell compositions and methods useful for treating autoimmune diseases (e.g., Type I diabetes).
Core Innovation
The disclosed invention relates to chimeric antigen receptor (CAR) constructs targeted to CD6. A CAR includes a single chain variable fragment targeted to CD6 comprising an amino acid sequence selected from SEQ ID NO: 38, 39, 40 and 41, together with a spacer comprising the amino acid sequence of SEQ ID NO: 91.
The CAR further includes a transmembrane domain selected from a CD4 transmembrane domain comprising the amino acid sequence of SEQ ID NO: 23, a CD8 transmembrane domain comprising the amino acid sequence of SEQ ID NO: 25, and a CD28 transmembrane domain comprising the amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 8. The CAR also includes a CTLA4 co-stimulatory domain comprising the amino acid sequence of SEQ ID NO: 17 and a CD3 zeta signaling domain comprising the amino acid sequence of SEQ ID NO: 92.
The disclosure contextualizes these CARs in regulatory T cell (Treg) formats and provides phenotype-marker options including CD4+CD25high, CD127low/negative, and CD6low/negative. The invention emphasizes therapeutic use in autoimmune diseases such as Type I diabetes, GvHD, and lupus, and describes CAR Tregs with CTLA4 signaling as outperforming in suppressing Teff proliferation.
Claims Coverage
The document includes two independent claims. Both independent claims cover CD6-targeted CARs with defined sequence-based modular components, and dependent claims further specify allowable sequence embodiments and regulatory T cell phenotype/marker constraints. Across the independent claims, there are five principal inventive features.
CD6-targeted CAR defined by scFv, spacer, transmembrane, CTLA4, and CD3 zeta sequences
A nucleic acid molecule encoding a chimeric antigen receptor (CAR) comprising a single chain variable fragment targeted to CD6 comprising an amino acid sequence selected from SEQ ID NO: 38, 39, 40 and 41; a spacer comprising the amino acid sequence of SEQ ID NO: 91; a transmembrane domain selected from the group consisting of a CD4 transmembrane domain comprising SEQ ID NO: 23, a CD8 transmembrane domain comprising SEQ ID NO: 25, and a CD28 transmembrane domain comprising SEQ ID NO: 7 or SEQ ID NO: 8; a CTLA4 co-stimulatory domain comprising SEQ ID NO: 17; and a CD3 zeta signaling domain comprising SEQ ID NO: 92.
CD6-targeted CAR defined by scFv, spacer, transmembrane, CTLA4, and CD3 zeta sequences
A chimeric antigen receptor (CAR) comprising a single chain variable fragment targeted to CD6 comprising an amino acid sequence selected from SEQ ID NO: 38, 39, 40 and 41; a spacer comprising the amino acid sequence of SEQ ID NO: 91; a transmembrane domain selected from the group consisting of a CD4 transmembrane domain comprising SEQ ID NO: 23, a CD8 transmembrane domain comprising SEQ ID NO: 25, and a CD28 transmembrane domain comprising SEQ ID NO: 7 or SEQ ID NO: 8; a CTLA4 co-stimulatory domain comprising SEQ ID NO: 17; and a CD3 zeta signaling domain comprising SEQ ID NO: 92.
Across the two independent claims, the coverage centers on CD6-targeted CARs and nucleic acid encoding such CARs built from explicitly identified sequence options for the CD6 single chain variable fragment, the spacer, one of specified CD4/CD8/CD28 transmembrane domains, a CTLA4 co-stimulatory domain, and a CD3 zeta signaling domain. Dependent claims further narrow permitted sequence embodiments and relate the CAR to regulatory T cell populations defined by marker-based phenotype proportions.
Stated Advantages
Inhibit pro-inflammatory CD6+ immune activity.
Avoid damage from beta-cell targeting.
Reduce activation.
Reduce cytokine release syndrome.
Reduce T-cell exhaustion.
Improve persistence/half-life.
CAR Tregs with CTLA4 signaling outperform in suppressing Teff proliferation.
Documented Applications
Treating autoimmune disease by administering engineered T lymphocytes/Tregs expressing the disclosed CD6-targeted CAR.
Autoimmune diseases, notably Type 1 diabetes.
Therapeutic use in autoimmune diseases, including Type I diabetes, GvHD, and lupus, using CD6 CARs in regulatory T cells with CTLA4 signaling.
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