Single-domain antibodies against CLL1 and constructs thereof
Inventors
Zhang, Wang • LIU, Yunlei • TU, Xiaojie • SHU, Chenyu • ZHAN, Tailan • Zhang, Yun • TANG, An • ZHANG, Yafeng • Wu, Shu • Zhang, Qing
Assignees
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Publication Number
US-12097219-B2
Publication Date
2024-09-24
Expiration Date
Abstract
Provided are single-domain antibodies targeting CLL1 and constructs thereof, including chimeric receptors, immune effector cell engagers and immunoconjugates. Further provided are engineered immune effector cells (such as T cells) comprising an anti-CLL1 chimeric receptor and optionally a second chimeric receptor targeting a second antigen or epitope. Pharmaceutical compositions, kits and methods of treating cancer are also provided.
Core Innovation
The invention relates to anti-CLL1 constructs comprising a single domain antibody (sdAb)-moiety that specifically binds to CLL1. The sdAb moiety is defined by CDR1, CDR2, and CDR3 amino acid sequences provided as multiple alternative SEQ ID NO combinations, including a defined CDR1 of SEQ ID NO: 165, a CDR2 of SEQ ID NO: 167, and a CDR3 of SEQ ID NO: 169.
The document also describes anti-CLL1 sdAb variants centered on CDR1/2/3 (SEQ ID NO:165/167/169), tolerated amino-acid substitutions/variants, VHH FR identity ranges referenced to VHH sequences (SEQ ID NOs:94-106, 171-173), and isolated sdAb/polypeptides for enumerated SEQ ID NOs (SEQ ID NOs:94-106 and 171-173). It includes epitope mapping and competition with CLL1-binding antibodies to define anti-CLL1 epitopes.
The invention extends to chimeric receptor and CAR architectures using anti-CLL1 sdAbs, including extracellular domain, transmembrane domain, and intracellular signaling domain components for single-, multi-, and multispecific receptor systems. It further covers dual and split chimeric receptor systems, immune effector cell engagers, multivalent targeting concepts, immunoconjugates/ADCs, and detection use-cases for labeled anti-CLL1 sdAbs.
Claims Coverage
The independent claim covers anti-CLL1 constructs where a single sdAb-moiety specifically binds CLL1, with the sdAb defined by one of multiple enumerated sets of CDR1/CDR2/CDR3 amino acid sequences.
Anti-CLL1 construct with CLL1-specific sdAb CDR set enumeration
An anti-CLL1 construct comprising a single domain antibody (sdAb)-moiety that specifically binds to CLL1, wherein the sdAb moiety comprises a CDR1, a CDR2, and a CDR3 defined by one of multiple provided amino acid sequence combinations (SEQ ID NO sets).
Overall, the claim coverage centers on the CLL1-specific sdAb-moiety defined by enumerated CDR1/CDR2/CDR3 amino acid sequence sets, with the provided information also referring to dependent claim refinements into receptor, multispecific, and conjugate/detection formats.
Stated Advantages
Documented Applications
Engineered immune cells incorporating anti-CLL1 sdAb into chimeric receptor architectures, including dual, tandem, and split CAR architectures.
Binding and functionality evaluation of the anti-CLL1 sdAb and engineered constructs using ELISA, FACS, SPR/BIAcore, and cytotoxicity/cytokine readouts.
In vivo tumor-model efficacy and toxicity assessment, including xenograft efficacy, tumor-free kinetics, and toxicity assessments in humanized immune system mice and non-human primates.
Cancer treatment, including AML.
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