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Multi-specific antibodies and methods of making and using thereof

A specific, binding-specific technology, applied in chemical instruments and methods, antibodies, specific peptides, etc.

Pending Publication Date: 2020-02-14
SYSTIMMUNE INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In a case study of patients resistant to blinatumumab, a second round of blinatumumab was administered, but with the addition of a monoclonal agent that was specific for PD-1 and blocked the interaction of PD-1 expressed by T cells with PD-L1 expressed by tumor cells. The cloned antibody Pembrolizumab (Keytruda, Merck), resulted in a significant response and reduction of tumor cells in the bone marrow from 45% to less than 5% in this patient (Feucht et al., 2016, Oncotarget 7(47):76902-76919)

Method used

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  • Multi-specific antibodies and methods of making and using thereof
  • Multi-specific antibodies and methods of making and using thereof
  • Multi-specific antibodies and methods of making and using thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] Embodiment 1: Take PBMC (peripheral blood mononuclear cell) as effector and B-acute lymphoblastic leukemia (B-ALL) cell Redirected T cell cytotoxicity (RTCC) assay targeting the cell lines Kasumi-2 and NALM-6

[0102]The tetraspecific antibodies listed in Table 1 and Table 2 were tested for RTCC activity against the B-ALL cell lines Kasumi-2 and Nalm-6 using human PBMC as effectors. Both Kasumi-2 and Nalm-6 target cells were previously transfected with green fluorescent protein (GFP) and FACS sorted to generate a cell population in which greater than 99% expressed GFP. GFP+Kasumi-2 and GFP+Nalm-6 cells were counted and set to a density of 100,000 cells / ml in assay medium. Human PBMCs were counted and the density was set at 100,000 cells / ml. Antibodies were prepared at 2X final concentration and titrated 1:10 in assay medium in six wells of a 96-well plate. In target 96-well plates, target cells, PBMCs, and serially titrated antibodies were pooled by adding 50 μl ta...

Embodiment 2

[0103] Example 2: Use of CD19-specific GNC antibody against interferon-γ and granzyme B in the 8th day RTCC culture supernatant ELISA analysis.

[0104] Thaw supernatants from wells stored at -80 °C and analyze for interferon gamma and particles using the g-IFN and GrB kits from R&D Systems (No. DY285B and No. DY2906-05) according to the manufacturer's recommended protocol Enzyme B levels. Will be Quantured TM Enhanced chemiluminescent HRP substrate (ThermoFisher Scientific No. 15159) was added to each well of the ELISA plate and used according to the manufacturer's instructions. As shown in Figure 6, the bispecific 21D4×284A10 induced high levels of IFN-γ secretion in PBMCs at 50pM antibody, which was almost the same as the tetraspecific antibody SI-34E34, while the other tetraspecific antibodies SI-34E35 and 36 as well as bispecific HD37×I2C did induce PBMC IFN-γ secretion, but at much lower levels. As shown in Figure 6, the bispecific 21D4×284A10 induced high levels ...

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Abstract

The disclosure provides a tetra-specific antibody monomer having a N-terminal and a C-terminal, comprising in tandem from the N-terminal to the C-terminal, a first scFv domain at the N-terminal, a second scFv domain, a Fab domain, a Fc domain, and a third scFv at the C-terminal, wherein the first scFv domain, the second scFv domain, the Fab domain, and the third scFv domain each has a binding specificity against a different antigen. In one embodiment, the antigen is a tumor antigen, an immune signaling antigen, or a combination thereof. In one embodiment, the antigen includes CD19, CD3, CD137,4-1BB, and PD-L1. Multi-specific antibodies comprising the disclosed tetra-specific antibodies are also provided.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Patent Application No. 62524558, filed June 25, 2017, which is expressly incorporated herein by reference in its entirety. technical field [0003] The present disclosure relates generally to the field of biotherapeutics, and more specifically to making and using multispecific antibodies. Background technique [0004] Cancer cells develop various strategies to evade the immune system. One of the mechanisms underlying immune evasion is reduced recognition of cancer cells by the immune system. Defective presentation of cancer-specific antigens, or their lack thereof, leads to immune tolerance and cancer progression. In the presence of efficient immune recognition, tumors use other mechanisms to avoid elimination by the immune system. Immunocompetent tumors create an inhibitory microenvironment that downregulates the immune response. Multiple players are involved...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C07K16/30A61K47/65A61K39/395
CPCC07K16/2803C07K16/2809C07K16/2878C07K16/2827C07K2317/31C07K2317/622C07K2317/55C07K2317/52C07K2317/60C07K2317/92A61K2039/505C07K2317/64C07K2317/66C07K2317/73C07K16/00A61P35/00A61K35/16A61K45/06C07K16/32
Inventor 朱义欧勒·奥尔森夏冬大卫·耶利曼卡特里娜·贝科娃安妮玛丽·卢梭比尔·布雷迪布莱尔·伦肖布莱恩·科瓦切维奇梁玉高泽人
Owner SYSTIMMUNE INC
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