Chimeric antigen receptors against AXL or ROR2 and methods of use thereof
Inventors
Frost, Gregory Ian • Onuffer, Jr., James Joseph • Short, Jay M. • Frey, Gerhard • Chang, Hwai Wen
Assignees
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Publication Number
US-12187801-B2
Publication Date
2025-01-07
Expiration Date
Abstract
The present disclosure provides chimeric antigen receptors that bind to Axl and Ror2, and conditionally active chimeric antigen receptors (CARs) that recognize Axl and Ror2. Furthermore, provided herein are nucleic acids encoding these CARs and methods of making and using the CARs, including methods of treating cancer, especially cancers that express Axl and/or Ror2, such as renal cell carcinoma. The present disclosure provides cells genetically modified to produce the CARs.
Core Innovation
The patent describes chimeric antigen receptors (CARs) that conditionally activate through recognition associated with Axl and/or Ror2. It provides nucleic acids encoding the CARs and engineered immune cells for cancer therapy, with conditional activation behavior within a tumor microenvironment.
A stated problem addressed in the disclosure is on-target off-tumor effects, and the motivation for conditional CAR activation is to reduce such effects. The disclosure links conditional activation to higher binding and activation at tumor-like acidic pH versus normal pH, including examples comparing pH 6.7 versus pH 7.4.
The CAR architecture described includes an antigen-specific targeting region (ASTR) such as an scFv or antibody fragment, a transmembrane domain, and an intracellular activating domain that can include CD3ζ and ITAM motifs. The disclosure further specifies optional co-stimulatory domains and modulatory features connected by linkers and stalk/hinge domains, while also describing elimination/recognition features separated by a ribosomal skip/cleavage concept.
Claims Coverage
The provided independent claim set comprises two independent nucleic-acid claims, both directed to a CAR binding Axl and sharing the same core architectural requirement: an ASTR with defined heavy-chain and light-chain variable CDR sequences plus a transmembrane domain positioned between the ASTR and an intracellular activating domain.
Axl-binding CAR nucleic acid with defined heavy- and light-chain CDRs
A nucleic acid encoding a chimeric antigen receptor for binding Axl, comprising an antigen-specific targeting region (ASTR) in which the ASTR binding to Axl comprises a heavy chain variable region with three complementarity determining regions having H1, H2, and H3 sequences and a light chain variable region with three complementarity determining regions having L1, L2, and L3 sequences, including H1 as X1GX2TMN (SEQ ID NO:87), H2 as LIKPSNGGTSYNQKFKG (SEQ ID NO:88), H3 as GX3YX4SYX5AMDY (SEQ ID NO:89), L1 as KASQDVX6SAVA (SEQ ID NO:90), L2 as WX7X8TRX9T (SEQ ID NO:91), and L3 as QEHFSX10PLX11 (SEQ ID NO:92) with X1–X11 allowed substitutions as defined.
Transmembrane domain positioned between ASTR and intracellular activating domain
A nucleic acid encoding a chimeric antigen receptor for binding Axl further comprising a transmembrane domain and an intracellular activating domain, wherein the transmembrane domain is located between the ASTR and the intracellular activating domain.
Across both independent claims, coverage centers on nucleic acids encoding an Axl-binding CAR whose ASTR contains specifically defined heavy-chain and light-chain CDR sequences (with constrained amino-acid substitutions expressed as X1–X11) and whose CAR architecture includes a transmembrane domain positioned between the ASTR and an intracellular activating domain.
Stated Advantages
Reduce on-target off-tumor effects by enabling conditional CAR activation behavior linked to higher binding/activation at tumor-like acidic pH versus normal pH.
Conditionally active Axl/Ror2 CAR activity and binding are enabled to be different under tumor-relevant conditions, including increased binding at tumor-relevant pH compared with physiological pH.
On-target off-tumor toxicity is addressed by modulating CAB-CAR binding and immune activation through microenvironment pH changes.
The disclosure states increased cytotoxicity and cytokine induction at reduced pH for Axl- and Ror2-directed CAB-CARs.
Documented Applications
CAR constructs and conditionally active ASTRs are applied in the context of tumor microenvironment targeting, including differentiation of activity and binding under tumor acidity and other described microenvironment drivers.
CAB-CARs with pH-differential binding and killing are described for Axl- and Ror2-directed activity in the tumor microenvironment, including in vitro and in vivo xenograft contexts.
Use of pH-modulating pharmacologic agents is described to modulate CAB-CAR binding and mitigate on-target off-tumor toxicity in blood and tissue microenvironment conditions.
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