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Publication Number
US-11845793-B2
Publication Date
2023-12-19
Expiration Date
Abstract
The present invention relates to a human or humanized antibody, or an antibody-based binding protein, modified antibody format retaining target binding capacity, antibody derivative or fragment retaining target binding capacity, which targets Receptor tyrosine kinase-like orphan receptor-1 (ROR1). It further relates to bi- or multispecific antibodies, to Immunoligand-Drug Conjugates, to Chimeric Antigen Receptors and to T-cells comprising such Chimeric Antigen Receptors.
Core Innovation
The disclosure relates to humanized antibody, antibody derivative or antibody fragment retaining target binding capacity that targets Receptor tyrosine kinase-like orphan receptor-1 (ROR1). The humanized antibody is defined by three heavy chain CDR sequences consisting of amino acid sequences SEQ ID NO: 29 (CDR1 HC), SEQ ID NO: 30 (CDR2 HC), and SEQ ID NO: 31 (CDR3 HC), and by three light chain CDR sequences consisting of amino acid sequences SEQ ID NO: 32 (CDR1 LC), SEQ ID NO: 33 (CDR2 LC), and SEQ ID NO: 34 (CDR3 LC). The heavy chain variable region sequence is at least 95% identical to sequences selected from SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, and SEQ ID NO: 43, and the light chain variable region sequence is at least 95% identical to sequences selected from SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, and SEQ ID NO: 44.
The disclosure further provides Immunoligand-Drug Conjugates having the general formula A-(L)n-(T)m, where A is a humanized antibody selected from huR12-4, huR12-7, huR12-11, and huR12-16, L is a linker, and T is a toxin, with n and m being integers between 1 and 10. The disclosed conjugate concept includes site-specific conjugation using sortase-mediated (SMAC) technology with sortase recognition tags and oligoglycine-modified toxins, and the toxin/linker options include PNU-derived anthracyclins and other toxin classes.
Beyond conjugates, the disclosure covers bispecific/multispecific antibody formats and CAR constructs using the ROR1-targeting antibody-derived binding domain. Therapeutic use is described in neoplastic diseases, including ROR1-positive settings, and the document reports generation and selection of humanized anti-ROR1 monoclonal antibodies via Transpo-mAb display and screening using FACS/SPR, with improved binding affinity for humanized R12 variants versus parental R12.
Claims Coverage
The independent claims cover two inventive feature groups: defined humanized anti-ROR1 antibodies with specific CDR sequences and highly humanized variable-region identity constraints, and Immunoligand-Drug Conjugates with an A-(L)n-(T)m architecture using selected huR12 antibodies, with one independent claim also restricting the toxin to a PNU-derived anthracycline.
Humanized antibody targeting ROR1 with defined heavy and light CDRs and highly humanized variable regions
A humanized antibody, antibody derivative or antibody fragment retaining target binding capacity that targets ROR1, comprising three heavy chain CDR sequences consisting of amino acid sequences SEQ ID NO: 29 (CDR1 HC), SEQ ID NO: 30 (CDR2 HC), and SEQ ID NO: 31 (CDR3 HC), and three light chain CDR sequences consisting of amino acid sequences SEQ ID NO: 32 (CDR1 LC), SEQ ID NO: 33 (CDR2 LC), and SEQ ID NO: 34 (CDR3 LC), with a heavy chain variable region sequence at least 95% identical to a sequence selected from SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, and SEQ ID NO: 43, and a light chain variable region sequence at least 95% identical to a sequence selected from SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, and SEQ ID NO: 44.
Immunoligand-Drug Conjugate with A-(L)n-(T)m architecture using selected huR12 antibodies
An Immunoligand-Drug Conjugate having the general formula A-(L)n-(T)m, in which A is a humanized antibody selected from huR12-4, huR12-7, huR12-11, and huR12-16, L is a linker, and T is a toxin, wherein n and m are integers between 1 and 10.
Immunoligand-Drug Conjugate with PNU-derived anthracycline toxin and defined variable-region sequences
An Immunoligand-Drug Conjugate having the general formula A-(L)n-(T)m, in which A is a humanized anti-ROR-1 antibody comprising at least one heavy chain variable region that comprises a sequence selected from SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, and SEQ ID NO: 43, and at least one light chain variable region that comprises a sequence selected from SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, and SEQ ID NO: 44, L is a linker, and T is a PNU-derived anthracycline, wherein amino acid sequences of A, of L, if comprising amino acids, and of T, if comprising amino acids, are from N-terminus to C-terminus, and wherein n and m are integers between 1 and 10.
The claims focus on defined humanized anti-ROR1 antibodies characterized by specific CDR sequences and highly similar variable-region sequences, and on Immunoligand-Drug Conjugates built on an A-(L)n-(T)m format where the antibody component is restricted to the huR12 set and, in one independent claim, the toxin component is restricted to a PNU-derived anthracycline.
Stated Advantages
Improved binding affinity for humanized R12 variants versus parental R12.
Target-mediated ADC cytotoxicity in ROR1-positive cell lines.
Prolonged survival in a disseminated xenograft mouse model using a SMAC-conjugated hu2A2b-Q11 ADC versus isotype control.
Documented Applications
Therapeutic use in neoplastic diseases, including ROR1-positive settings.
CAR constructs using the ROR1-targeting antibody-derived binding domain.
Immunoligand-Drug Conjugates/ADCs targeting ROR1 for cytotoxic effects in ROR1-positive cell lines and in a disseminated xenograft mouse model.
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