Binding protein-toxin conjugates comprising anthracyclines, and use thereof in immune-oncological applications

A technology for binding proteins and conjugates, which is applied in the field of binding protein-toxin conjugates, and can solve problems such as no efficacy

Pending Publication Date: 2021-05-14
NBE THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Also shown to exist tumor types for which immune checkpoint inhibitors are not effective

Method used

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  • Binding protein-toxin conjugates comprising anthracyclines, and use thereof in immune-oncological applications
  • Binding protein-toxin conjugates comprising anthracyclines, and use thereof in immune-oncological applications
  • Binding protein-toxin conjugates comprising anthracyclines, and use thereof in immune-oncological applications

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Experimental program
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Embodiment approach

[0081] According to one embodiment of the present invention, the binding protein binds to at least one target selected from the group consisting of:

[0082] ·ROR1

[0083] ·CS1

[0084] ·HER2

[0085] Mesothelin (MN), and / or

[0086] ROR2.

[0087] Among them, ROR1 is a preferred target.

[0088] These targets and antibodies against them are described in the following publications:

[0089] · US2019112385A1 (mesothelin),

[0090] ·US2019153092A1, WO2019016381(ROR1),

[0091] ·WO2019030240A1(CS-1),

[0092] · US2018028682 (HER2) and

[0093] · WO2019016392A1 (ROR2),

[0094] Its content is incorporated herein by reference.

[0095] Preferably, said target is of human origin. In particular, when referred to herein, ROR1 preferably refers to human ROR1.

[0096] The term "immune checkpoint inhibitor" as used herein refers to any binding agent or compound suitable to act against an immune checkpoint protein. In particular, "immune checkpoint inhibitor" refers to any ...

Embodiment 1

[0258] Example 1. Production of purified, recombinant anti-human ROR1 and isotype control antibodies

[0259] Expression vectors: antibody variable region coding regions were generated by total gene synthesis (GenScript), using MNFGLRLIFLVLTLKGVQC as a leader sequence, and human IgH-γ1 and IgL-κ or IgL-λ constant regions as appropriate in expression vector pCB14 Assemble. This vector is a derivative of the episomal mammalian expression vector pCEP4 (Invitrogen), carries the EBV origin of replication, encodes the EBV nuclear antigen (EBNA-1) to allow extrachromosomal replication, and contains a puromycin selectable marker in place of the initial tide Mycin B resistance gene.

[0260] Expression and purification: The pCB14-based expression vector was transfected into HEK293T cells, using LTX reagent with PLUS TM (Thermo Fisher Scientific, Reinach, Switzerland, 15388100); followed by incubation for 1 day (37°C, 5% CO 2 , growth medium: Duchenne's modified Eagle medium (DMEM)...

Embodiment 2

[0265] Example 2. SMAC-Technology for mAbs TM Conjugation of glycine modified toxins to form ADCC

[0266] Sortase A. According to the technique described in WO2014140317A1, the recombinant and affinity-purified sortase A based on Staphylococcus aureus was produced in Escherichia coli.

[0267] Production of glycine-modified toxins. For the production of SMAC-technologies TM The conjugated ADC, Pentaglycine-EDA-PNU derivative (G5-EDA-PNU) was produced by Concortis (eg figure 1 shown). The identity and purity of the pentaglycine-modified toxin were confirmed by mass spectrometry and HPLC, respectively. G5-EDA-PNU showed >95% purity as determined by HPLC chromatography.

[0268] Sortase-mediated antibody conjugation. Conjugate antibodies to the above toxins according to Table 2: LPETG-tagged mAb [10 μM] with glycine-modified toxin [200 μM] and 3 μM sortase A in listed conjugation buffer at 25 °C Incubate for 3.5h. The reaction was terminated by passing it over a protein A ...

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Abstract

The present invention relates to binding protein-toxin conjugates comprising one or more anthracycline toxin moieties, and the use thereof in immunooncological applications.

Description

[0001] field of invention [0002] The present invention relates to binding protein-toxin conjugates comprising one or more anthracycline toxoid moieties, and their use in immuno-oncology applications. Background technique [0003] Binding protein-toxin conjugates, with antibody-drug conjugates (ADCs) as their most prominent representatives, have a great impact on cancer therapy, providing new therapeutic approaches for hitherto untreatable tumor types. [0004] On the other hand, the discovery of immune checkpoints and the development of immune checkpoint inhibitors make the role of the immune system in cancer treatment and methods of stimulating the immune system or overcoming immune checkpoints (which individual tumors use for self-protection against immune system attacks) In focus again. [0005] Although these two approaches are hotly discussed and represent major advances in cancer treatment, it is also clear that there are tumor types that cannot be treated with these ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/68A61P35/00
CPCA61K47/6809A61K47/6851A61K47/6889A61P35/00A61K47/6817A61K31/65
Inventor U·格劳乌德R·贝利L·瓦尔德迈尔F·普雷托
Owner NBE THERAPEUTICS
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