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Multispecific antibodies, multispecific activatable antibodies and methods of using the same

A multi-specific and specific technology, applied in chemical instruments and methods, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, specific peptides, etc. The therapeutic use of clonal antibodies, etc.

Active Publication Date: 2016-06-29
CYTOMX THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, targeting or neutralizing a single protein is not always sufficient to effectively treat certain conditions, limiting the therapeutic use of monospecific monoclonal antibodies
Furthermore, antibody-based therapies have proven effective in treating some diseases, but in some cases, toxicity resulting from broad target expression limits their therapeutic efficacy
In addition, antibody-based therapies have shown other limitations, such as rapid clearance from circulation after administration

Method used

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  • Multispecific antibodies, multispecific activatable antibodies and methods of using the same
  • Multispecific antibodies, multispecific activatable antibodies and methods of using the same
  • Multispecific antibodies, multispecific activatable antibodies and methods of using the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0530] Example 1: Preparation of multispecific antibodies

[0531] This example shows the construction, expression and purification of anti-Jagged-CD3, anti-Jagged-CTLA-4, anti-EGFR-CD3 and anti-EGFR-CTLA-4 multispecific antibodies.

[0532] The anti-Jagged (4D11v2) heavy chain, 5342-1204-4D11v2 light chain, anti-EGFRC225v5 heavy chain and 3954-1204-C225v5 light chain sequences shown above were expressed using vectors. Such vectors are described in co-pending applications PCT / US2013 / 038540, filed April 26, 2013 (title "Activatable Antibodies That Bind Epidermal Growth Factor Receptor And Methods Of Use Thereof") and PCT / US2013 / 047109, filed June 21, 2013 (title "Anti-Jagged Antibodies, Activatable Anti-Jagged Antibodies and Methods of Use Thereof"), the contents of each of which are incorporated herein by reference in their entirety.

[0533] The vector was digested with restriction enzymes NheI and NotI, and the vector fragments were separated by gel electrophoresis. Inse...

Embodiment 2

[0540] Example 2: Preparation of multispecific antibodies and multispecific activatable antibodies

[0541] Fully human IgG was expressed from transiently transfected HEK-293 cells. Co-transfection with the different heavy and light chain expression vectors shown in Table 10 enabled the expression of multispecific activatable antibodies.

[0542] Table 10

[0543] Transfection number

light chain carrier

heavy chain carrier

1

Anti-EGFR C225v5 LC

C225v5-OKT3 HC

97 --> 2

3954-1204-C225v5 LC

C225v5-OKT3 HC

3

C225v5 LC

C225v5-CTLA HC

4

3954-1204-C225v5 LC

C225v5-CTLA HC

5

Anti-Jagged 4D11v2 LC

4D11v2-OKT3 HC

6

5342-1204-4D11v2 LC

4D11v2-OKT3 HC

7

4D11v2 LC

4D11v2-CTLA HC

8

5342-1204-4D11v2 LC

4D11v2-CTLA HC

[0544]Multispecific antibodies and multispecific activatable antibodies expressed in HEK-293 cells were purified by protein A chrom...

Embodiment 3

[0548] Example 3: OKT3 binds to CD3ε

[0549] Such as Figure 13 As shown in , ELISA-binding experiments revealed that anti-EGFR multispecific activatable antibody 3954-1204-C225v5-OKT3 and anti-Jagged multispecific activatable antibody 5342-1204-4D11v2-OKT3 specifically bound human CD3ε. Human CD3ε (NovoProtein, Cat#C578) was adsorbed to the wells of a 96-well ELISA plate. The purified anti-EGFR multispecific activatable antibody 3954-1204-C225v5-CTLA-4, anti-EGFR multispecific activatable antibody 3954-1204-C225v5-OKT3, anti-Jagged multispecific activatable antibody 5342- 1204-4D11v2-CTLA-4 or anti-Jagged multispecific activatable antibody 5342-1204-4D11v2-OKT3 was applied to the plate and allowed to bind. Bound antibody was visualized with anti-human IgG-HRP conjugate (Fab-specific, Sigma, St Louis, MO; Cat#A0293-1ML) and developed with the chromogenic substrate TMB.

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PUM

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Abstract

The invention relates generally to multispecific antibodies and to multispecific activatable antibodies that specifically bind to two or more different antigens or epitopes, as well as to methods of making and using these multispecific antibodies and / or multispecific activatable antibodies in a variety of therapeutic, diagnostic and prophylactic indications.

Description

[0001] related application [0002] This application claims the benefit of US Provisional Application No. 61 / 858,402, filed July 25, 2013, the contents of which are hereby incorporated by reference in their entirety. field of invention [0003] The present invention generally relates to multispecific antibodies and multispecific activatable antibodies that specifically bind two or more different targets or epitopes, and to the preparation and use of these multispecific antibodies in various therapeutic, diagnostic and prophylactic indications. Methods of specific antibodies and / or multispecific activatable antibodies. Background of the invention [0004] Monoclonal antibodies have emerged as molecules for therapeutic intervention in a variety of conditions. However, targeting or neutralizing a single protein is not always sufficient to effectively treat certain conditions, which limits the therapeutic use of monospecific monoclonal antibodies. Furthermore, antibody-based t...

Claims

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Application Information

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IPC IPC(8): C07K16/28
CPCC07K16/2809C07K16/2818C07K16/2896C07K2317/31C07K2317/50C07K2317/622C07K2317/64C07K2317/73C07K2317/92C07K16/2863A61P35/00C07K16/2803C07K16/468
Inventor B.A.欧文D.R.霍斯特特C.王H.B.罗曼J.W.韦斯特S.L.拉波特
Owner CYTOMX THERAPEUTICS
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