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Trivalent trispecific antibody constructs

A specific and antigenic technology, applied in the direction of antibodies, specific peptides, anti-tumor drugs, etc., can solve the problems of poor expression and folding of antibody chains, poor stability of assembled antibodies, complex in vitro assembly reactions or purification methods, etc.

Pending Publication Date: 2021-02-19
INVENRA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, antibody chain engineering can lead to poor stability of assembled antibodies, poor expression and folding of antibody chains, and / or production of immunogenic peptides
Other methods suffer from impractical manufacturing processes, such as complex in vitro assembly reactions or purification methods
Furthermore, several platforms suffer from the inability to easily and efficiently insert different antibody binding domains

Method used

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  • Trivalent trispecific antibody constructs
  • Trivalent trispecific antibody constructs
  • Trivalent trispecific antibody constructs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0425] 6.13.2. Example 1: Bivalent monospecific and bivalent bispecific constructs

[0426] A bivalent monovalent monovalent recognizing TNFα was constructed using standard molecular biology procedures following the following architecture (VL(certolizumab)-CH3(knob)-CH2-CH3 / VH(certolizumab)-CH3(hole)) Specific B-Body. In this construct,

[0427] First polypeptide chain (SEQ ID NO: 1)

[0428] Domain A = VL (certolizumab)

[0429] Domain B = CH3 (IgG1) (Knob: S354C+T366W)

[0430]Domain D = CH2 (IgG1)

[0431] Domain E = CH3 (IgG1)

[0432] Second polypeptide chain (SEQ ID NO:2)

[0433] Domain F = VH (certolizumab)

[0434] Domain G=CH3 (IgG1) (holes: Y349C, T366S, L368A, Y407V)

[0435] The third polypeptide chain:

[0436] Same as the first polypeptide chain

[0437] The fourth polypeptide chain:

[0438] Same as the second polypeptide chain.

[0439] Domain and polypeptide chain references conform to image 3 . The entire construct architecture is in Figure ...

Embodiment 2

[0448] 6.13.3. Example 2: Bivalent bispecific B-Body "BC1"

[0449] We constructed a bivalent bispecific construct specific for PD1 and a second antigen "Antigen A", which we named "BC1". The salient features of the "BC1" architecture are Image 6 shown in .

[0450] In more detail, the architecture (with image 3 The domain and polypeptide chain references and modifications of the native sequence indicated in brackets) are:

[0451] First polypeptide chain (SEQ ID NO:8)

[0452] Domain A=VL("Antigen A")

[0453] Domain B = CH3 (T366K; 445K, 446S, 447C tripeptide insertion)

[0454] Domain D=CH2

[0455] Domain E=CH3 (T366W, S354C)

[0456] Second polypeptide chain (SEQ ID NO:9):

[0457] Domain F = VH ("Antigen A")

[0458] Domain G=CH3 (L351D; 445G, 446E, 447C tripeptide insertion)

[0459] Third polypeptide chain (SEQ ID NO: 10):

[0460] Domain H = VL ("Nivo")

[0461] Domain I = CL(κ)

[0462] Domain J=CH2

[0463] Domain K=CH3 (Y349C, D356E, L358M, T366S, L...

Embodiment 6

[0534] 6.13.7. Embodiment 6: Variable CH3 connection engineering

[0535] We generated a series of variants in which we mutated the VL-CH3 linkage between domain A and domain B and the VH-CH3 linkage between domain F and domain G to evaluate bivalent 1x1 B-Body construction The expression level, assembly and stability of the body. Although many solutions are possible, in order to reduce the introduction of T-cell epitopes, we chose to use only residues found naturally within the VL, VH and CH3 domains. Structural evaluation of the domain architecture further constrains desired sequence combinations. Tables 2 and 3 below show linkages based on various linkage variants of "BC1" and other bivalent constructs.

[0536]

[0537]

[0538]

[0539]

[0540] Figure 20 shows the size exclusion chromatograms of "BC15" and "BC16" samples at 40°C for the indicated weeks of the accelerated stability testing protocol. "BC15" remained stable; "BC16" proved to be unstable over ...

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PUM

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Abstract

Trispecific trivalent antibody constructs, pharmaceutical compositions comprising the constructs, and methods of use thereof are presented.

Description

[0001] 1. Cross references to related applications [0002] This application claims the benefit of and priority to US Divisional Application No. 62 / 659,047, filed April 17, 2018. The entire contents of the applications cited above are incorporated by reference. [0003] 2. Sequence Listing [0004] This application includes a Sequence Listing which has been submitted via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created in XX, 2019, is named XXXXXUS_sequencelisting.txt and is X,XXX,XXX bytes in size. [0005] 3. Background technology [0006] Antibodies are invaluable tools in the medical field. In particular, the importance of monoclonal antibodies, including their role in scientific research and medical diagnostics, has been widely recognized for decades. However, the full potential of antibodies, and in particular their successful use as therapeutic agents, has only recently been demonstrated, as demonstrated by the following succe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K47/68C07K16/46
CPCC07K16/2809C07K16/32C07K16/2878C07K2317/31A61P35/00C07K16/241C07K2317/526C07K2317/64C07K2317/71C07K2317/92C07K16/2818C07K16/468C07K2317/515C07K2317/522C07K2317/35A61K2039/505C07K2317/524
Inventor L·贝利B·格拉泽李曲飞R·格林D·K·普鲁库纳特M·A·诺库拉-鲁格维斯卡D·J·格哈特
Owner INVENRA INC