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Bispecific antibodies to ror1 and cd3

A technology of bispecific antibody and antibody molecule, applied in the field of bispecific antibody molecule and bispecific antibody, which can solve problems such as limited expression

Pending Publication Date: 2020-03-17
UCL BUSINESS PLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Receptor tyrosine kinase-like orphan receptor 1 (ROR1) (also known as neurotrophic tyrosine kinase, receptor-related 1, NTRKR1) is an oncoembryonic antigen expressed during embryogenesis but not in normal adult tissues Limited expression in

Method used

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  • Bispecific antibodies to ror1 and cd3
  • Bispecific antibodies to ror1 and cd3
  • Bispecific antibodies to ror1 and cd3

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0214] Materials and methods

[0215] ScFv generation

[0216] Rats were immunized with full-length ROR1 with Aldevron GmBH, oligoclonal clones from subsequent hybridomas were single-cell sorted, and variable sequences were isolated by 5' reverse amplification of cDNA ends using standard laboratory protocols. The production sequence was cloned into an antibody and assessed for specific binding to ROR1 before it was converted into a heavy chain-linker-light chain format single-chain variable fragment.

[0217] Cell Lines and Reagents

[0218] PANC-1, SKOV-3 and HEK293T cells were obtained from the American Type Culture Collection (ATCC; Teddington, Middlesex, UK). SUIT-2, CFPAC1, HPAF-II MiaPaCa-2, PSN-1 cell lines were developed by Professor Aldo Scarpa (Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy) ,Italy)) kindly provided. HEK293T cells were cultured in Iscove's Modified Dulbecco medium (ThermoScientific, Paisley, UK) su...

Embodiment 2

[0246] epitope mapping

[0247] To assess the epitopes of the antibodies produced, we generated cell lines with truncated ROR1: these cell lines contained SUPT1 cells expressing full-length ROR1 (Ig, Frizzled and Kringle domains), immunoglobulin Protein domain only SupT1 , Coiled domain only SupT1 , Kringle only SupT1 , and combinations (Ig and Frizzled domain SupT1 and Frizzled and Kringle domain SupT1 ). This indicates that clone F binds to the coiled domain. This differs from prior art antibodies R12 and 4A5 that bind immunoglobulin domains. Thus, clone F exhibits different and unique binding properties compared to prior art antibodies R12 and 4A5.

[0248] To further characterize the epitope to which clone F specifically binds, we compared rat ROR1 to human ROR1 to assess amino acid differences between these two species. We made a number of mutated human ROR1 constructs that included single amino acid substitutions to putative amino acids that these antibodies could bin...

Embodiment 3

[0252] Due to sequence homology, clone F is unique to other antibodies produced (mouse and rabbit)

[0253] Human, murine, rabbit, and rat ROR1 protein sequences were aligned using Uniprot web-based software (http: / / www.uniprot.org / align / ) and differences between species were highlighted. Uniprot accession numbers: human (Q01973), mouse (Q9Z139) and rabbit (G1U5L1). For rat ROR1, the NCBI reference sequence NP_001102141.1 was used since the corresponding Uniprot sequence is only partially complete.

[0254] Clone F binds to Q261, probably due to a difference between the rat and human amino acids at this position (the human amino acid at position 261 is glutamine (Q), while the corresponding amino acid at this position in rats is histamine Acid (H)). When immunizing rats with human ROR1, this amino acid difference is considered immunogenic relative to the sequence of rat ROR1 against which the antibody was raised.

[0255] Known binders of antibody R12 (rabbit) and murine RO...

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PUM

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Abstract

There is described bispecific antibodies which selectively bind to Receptor Tyrosine Kinase Like Orphan Receptor 1 (ROR1) and the CD3 subunit of the T-Cell Receptor (TCR), their production and their use. Also described is the use of the bispecific antibodies in the treatment of cancer.

Description

[0001] The present invention relates to a bispecific antibody selectively binding to receptor tyrosine kinase-like orphan receptor 1 (Receptor TyrosineKinase Like Orphan Receptor, ROR1) and CD3 subunit of T cell receptor (T-Cell Receptor, TCR). Background technique [0002] Receptor tyrosine kinase-like orphan receptor 1 (ROR1) (also known as neurotrophic tyrosine kinase, receptor-related 1, NTRKR1) is an oncoembryonic antigen expressed during embryogenesis but not in normal adult tissues limited expression. However, it is expressed on many hematological and solid malignancies: Chronic Lymphocytic Leukaemia (CLL), Acute Lymphoblastic Leukaemia (ALL), Mantle Cell Leukemia, Hairy Cell Leukemia, Pancreatic Cancer, Prostate Cancer, Colon cancer, bladder cancer, ovarian cancer, glioblastoma, testicular cancer, uterine cancer, adrenal gland cancer, breast cancer, lung cancer, melanoma, neuroblastoma, sarcoma, kidney cancer. Furthermore, ROR1 is expressed on a subset of cancer stem ...

Claims

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Application Information

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IPC IPC(8): C07K16/28A61P35/00
CPCC07K16/2803C07K16/2809A61K2039/505C07K2317/24C07K2317/31C07K2317/33C07K2317/34C07K2317/622C07K2317/73A61P35/00
Inventor 阿米特·纳什瓦尼萨蒂恩·戈希尔马可·德拉佩鲁塔
Owner UCL BUSINESS PLC
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