ROR1 antibody compositions and related methods
Inventors
Rader, Christoph • Peng, Haiyong • Beerli, Roger • Waldmeier, Lorenz • Grawunder, Ulf
Assignees
NBE Therapeutics AG • University of Florida • University of Florida Research Foundation Inc
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Publication Number
US-11242388-B2
Publication Date
2022-02-08
Expiration Date
Abstract
The invention provides antibodies, antibody drug conjugates, antibody-based fragments or antibody fragments (antigen-binding fragments), as well as antibody drug conjugates (ADCs) and chimeric antigen receptors (CARs), that specifically recognize human ROR1 and related compositions. Also provided in the invention are methods of using such antibodies in various diagnostic and therapeutic applications.
Core Innovation
The invention provides an antibody, antibody-based binding protein or antibody fragment that specifically binds to the extracellular domain of human receptor tyrosine kinase-like orphan receptor 1 (ROR1). The binding molecules are defined by particular heavy-chain and light-chain CDR sequences, comprising specified HCDR1, HCDR2 and HCDR3 sequences and LCDR1, LCDR2 and LCDR3 sequences.
The invention further provides a polynucleotide that encodes the antibody, antibody-based binding protein or antibody fragment comprising the specified HCDR1, HCDR2 and HCDR3 sequences and LCDR1, LCDR2 and LCDR3 sequences. Representative antibody embodiments include XBR1-402 and ERR1-TOP43, together with humanized forms generated by CDR grafting and chimeric rabbit/human Fab and chimeric rabbit/human IgG1 formats.
The invention also provides an antibody drug conjugate (ADC) using the ROR1-targeting antibody or antibody fragment defined by the specified heavy and light CDR sequences, together with at least one cytotoxic agent. The document states that ADC conjugation is performed using sortase enzyme mediated antibody conjugation (SMAC) and that anthracycline toxin derivatives are used, including PNU-159682 and Gly(n)-EDA-PNU.
The document further describes selective binding to the extracellular domain of ROR1 and diagnostic and therapeutic uses tied to detecting and targeting ROR1-expressing tumors, including imaging and detection of ROR1 levels.
Claims Coverage
The independent claims cover three invention categories: a defined ROR1-specific antibody-based binder, a polynucleotide encoding that defined CDR set, and an ADC that conjugates a cytotoxic agent to that defined ROR1-binding antibody. Across these categories, the claim set specifies a fixed CDR sequence set and, for the ADC, specifies cytotoxic agent and conjugation constraints.
Ror1 extracellular domain-binding antibody defined by specified CDR sequences
An antibody, antibody-based binding protein or antibody fragment that specifically binds to the extracellular domain of human receptor tyrosine kinase-like orphan receptor 1 (ROR1), comprising the specified HCDR1, HCDR2 and HCDR3 sequences and LCDR1, LCDR2 and LCDR3 sequences.
Polynucleotide encoding the specified CDR-defined Ror1-binding antibody or fragment
A polynucleotide encoding an antibody, antibody-based binding protein or antibody fragment comprising the specified HCDR1, HCDR2 and HCDR3 sequences and LCDR1, LCDR2 and LCDR3 sequences.
Adc with the specified CDR-defined Ror1-binding antibody and at least one cytotoxic agent
An antibody drug conjugate (ADC), comprising an antibody, antibody-based binding protein or antibody fragment that specifically binds to the extracellular domain of human receptor tyrosine kinase-like orphan receptor 1 (ROR1), comprising the specified heavy HCDR1, HCDR2 and HCDR3 sequences and LCDR1, LCDR2 and LCDR3 sequences, and at least one cytotoxic agent.
Smac-conjugated ADC using sortase enzyme mediated antibody conjugation
An antibody drug conjugate in which the antibody or antibody fragment is conjugated to a cytotoxic agent using sortase enzyme mediated antibody conjugation (SMAC).
Pnu anthracycline toxin derivative Gly(n)-EDA-PNU
An antibody-drug conjugate in which the cytotoxic agent is an anthracycline (PNU) toxin derivative Gly(n)-EDA-PNU.
Overall, the claim coverage is centered on a fixed CDR sequence set that defines ROR1 extracellular-domain binding, extended to a matching polynucleotide encoding that binder, and further extended to ADCs that attach a cytotoxic agent to the same CDR-defined ROR1 binder. The ADC embodiments also recite sortase enzyme mediated antibody conjugation (SMAC) and anthracycline toxin derivatives.
Stated Advantages
Higher potency of XBR1-402 and humanized forms in vitro and in vivo tumor models.
Documented Applications
Diagnostic and imaging uses for ROR1-expressing tumors, including detection of ROR1 levels and imaging of ROR1-expressing tumors.
Therapeutic treatment of disease or condition associated with elevated ROR1 expression by administering the pharmaceutical composition comprising the specified ROR1-binding antibody-based binder.
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