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Multimeric antibodies with enhanced selectivity to cells with high target density

A multimer and cell technology, applied in the direction of antibody medical components, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, anti-tumor drugs, etc.

Pending Publication Date: 2022-06-10
IGM BIOSCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, although treatment with this antibody can kill tumor cells, the antibody may also have adverse effects on normal cells
For example, the anti-CD20 monoclonal antibody rituximab is effective against B-cell lymphoma, but may also deplete the patient's normal B-cells

Method used

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  • Multimeric antibodies with enhanced selectivity to cells with high target density
  • Multimeric antibodies with enhanced selectivity to cells with high target density
  • Multimeric antibodies with enhanced selectivity to cells with high target density

Examples

Experimental program
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Effect test

Embodiment 1

[0209] Example 1: Modeling, Construction and Expression of Selectively Enhanced Affinity Altered Anti-CD20 IgM Antibodies to Malignant B Cells

[0210] Anti-CD20 antibodies (eg, rituximab) are widely used in the treatment of B cell malignancies (eg, lymphoma). Unfortunately, CD20 is also widely expressed on normal B cells, leading to undesired B cell depletion during anti-CD20 cancer therapy. Antigen expression is usually much higher density on malignant B cells than on normal B cells. This example shows the construction and characterization of a reduced affinity IgM antibody with an anti-CD20 binding domain. The increased affinity of IgM causes the antibody to selectively target those cells expressing CD20 at a higher density.

[0211] A pentameric or hexameric IgM antibody that can specifically bind to CD20 with reduced affinity relative to rituximab was prepared by the following method. In silico modeling of the VH (SEQ ID NO:7) and VL (SEQ ID NO:8) amino acid sequences ...

Embodiment 2

[0217] Example 2: Characterization of CD20 density on B cell lines

[0218] The relative CD20 surface density of the following B cell lines was tested using the QIFIKit (DAKO): Raji (ATCC Accession No. CCL-86), Ramos (ATCC Accession No. CRL-1596), CA46 (ATCC Accession No. CRL-1648), DB (ATCC accession number CRL-2289), DoHH-2 (DSMZ accession number ACC-47), JeKo-1 (ATCC accession number CRL-3006), Z-138 (ATCC accession number CRL-3001), Toledo (ATCC accession number CRL-2631), BJAB (DSMZ Accession No. ACC-757), Kasumi-2 (DSMZ Accession No. ACC-526), ​​Nalm-1 (ATCC Accession No. CRL-1567), RPMI 8226 (ATCC Accession No. CCL-155), HT (ATCC Accession No. CRL-2260), SU-DHL-8 (ATCC Accession No. CRL-2961) and JM1 (ATCC Accession No. CRL-10423). Unconjugated mouse CD20 antibody (Biolegend) was used at saturation point as primary antibody to achieve monovalent binding at 20 μg / mL. FITC-conjugated F(ab')2 antibody (Dako) was used as secondary antibody at 1:50. Populations of five ca...

Embodiment 3

[0225] Example 3: Binding activity of IgG and IgM anti-CD20 mutants on Ramos cells

[0226] The binding affinities of the various IgG and IgM anti-CD20 mutant IgG and IgM antibodies produced in Example 1 were measured by flow cytometry by the following method. at 37°C in 5% CO 2 Ramos cells were maintained in RPMI complete medium (RPMI-C; RPMI 1640 medium, 10 mM HEPES, 1 mM sodium pyruvate, 1x MEM non-essential amino acids, 1x GlutaMAX) containing 10% HI-fetal bovine serum in an incubator nourish. Cells were split every 2-3 days as needed to maintain a cell density of 0.2-2.0x10 6 cells / mL. Recover about 2x10 by centrifugation 6 cells, and resuspended in 4.0mL FACS staining buffer (FSB, BD 554656; 0.5x10 6 cells / mL). Purified IgG or IgM antibodies prepared as described in Example 1 were diluted to 20 μg / mL FBS and then serially diluted 3-fold in FSB in TC-untreated 96-well plates (Falcon 351177). Cells (25 μL, 12,500 cells / well) and serially diluted antibody samples (25...

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Abstract

The present disclosure provides a multimeric binding molecule, such as an IgM, IgM-like, IgA, or IgA-like binding molecule, such as an antibody with enhanced selectivity against cells expressing a target at a high density, such as tumor cells. Selective enhancement may be achieved, for example, by modulating binding affinity to the target antigen and / or by modulating affinity via multimeric antigen binding.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 62 / 902,915, filed September 19, 2019, which is hereby incorporated by reference in its entirety. [0003] sequence listing [0004] This application contains a Sequence Listing, which is filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy was created on September 17, 2020, named 023WO1-Sequence-Listing, and was 82,283 bytes in size. Background technique [0005] Monoclonal antibodies that directly target cancer cells and other diseased cells often bind to target antigens that are overexpressed on diseased cells but are also expressed at reduced levels on normal, healthy cells. Therefore, although treatment with such antibodies can kill tumor cells, the antibodies may also have adverse effects on normal cells. For example, the anti-CD20 monoclonal antibody rituximab (rituximab)...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P35/00A61P35/02A61P31/12C07K16/18C07K16/28A61K39/00
CPCC07K2317/52C07K16/2887C07K2317/92C07K2317/732C07K2317/73C07K2317/31C07K16/2809C07K2317/24C07K2317/55C07K2317/565C07K2317/35C07K2317/734A61P35/00C07K14/5443C07K14/7155C07K16/283C07K2317/622C07K2319/30
Inventor R·巴利加P·辛顿B·基特
Owner IGM BIOSCI INC
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