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Pharmaceutical preparation for use in treating epstein-barr virus positive patients with reactivation phenomenon-associated diseases

A technology of reactivation and disease, applied in antiviral agents, cell culture active agents, diseases, etc., can solve problems such as weak control, no disease treatment drugs, and unbalanced EBV immune response

Pending Publication Date: 2020-12-25
TRION RES +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0030] Taken together, available data suggest weaker control of existing EBV infection combined with genetic and other cofactors (eg, low vitamin D levels, other infections) or due to relatively late infection (eg, in adolescents or adults) The resulting imbalance of the immune response against EBV may induce a variety of autoimmune diseases
[0031] To date, there is no therapeutic drug for diseases associated with reactivation of EBV, and there is a need to provide a drug for treating patients with EBV reactivation in B cells

Method used

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  • Pharmaceutical preparation for use in treating epstein-barr virus positive patients with reactivation phenomenon-associated diseases
  • Pharmaceutical preparation for use in treating epstein-barr virus positive patients with reactivation phenomenon-associated diseases
  • Pharmaceutical preparation for use in treating epstein-barr virus positive patients with reactivation phenomenon-associated diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0151] Example 1. In vitro killing of enriched autologous B cells mediated by trifunctional bispecific antibodies

[0152] Example 1 demonstrates efficient killing of enriched autologous B cells targeted in vitro by a CD20-specific trifunctional bispecific antibody. 250,000 enriched B cells and 500,000 PBMCs from healthy donors were prepared as described in the Methods and Materials section. Cells were mixed and incubated in the presence or absence of 1 μg Bi20 as a trifunctional bispecific anti-CD3x anti-CD20 antibody ( figure 1 ). Incubate the cells at 37 °C and 5% CO 2 The culture medium (RPMI1640 medium supplemented with 8.9% FCS, 2 mM L-glutamine, 1 mM sodium pyruvate and 1× non-essential amino acids) was cultured in a total volume of 1 ml in a 24-well plate. Three days later, cells were analyzed by flow cytometry using FACS-Calibur and Cellquest pro software (Becton Dickinson, USA). B cells were stained by PE (phycoerythrin)-conjugated anti-human CD20 monoclonal anti...

Embodiment 2

[0153] Embodiment 2 (chronic fatigue syndrome, chronic dry cough, night sweats)

[0154] A 49-year-old woman who tested positive for EBV suffered from repeated episodes of fatigue for ten years, lymphedema, chronic otitis media, and frequent nocturnal sweating. In addition, the patient was diagnosed with pancreatitis in May 2010 and developed rectal cancer in July 2010. EBV was detected in tumor cells and subsequently in surgical scars by PCR analysis. Since 2000, the patient suffered from chronic dry cough.

[0155] In a detailed EBV diagnosis, for example, a high frequency of EBER-1+2 CISH positive B cells (>50%) together with slightly elevated IL-8 values ​​can be determined within the patient's enriched B cell fraction.

[0156] Because of this diagnosis and unmet medical need, the patient decided to enroll in compassionate use treatment with an investigational anti-EBV therapeutic vaccine.

[0157] For the preparation of vaccine cell preparations, 60 ml of peripheral b...

Embodiment 3

[0176] Example 3 (Insulin Resistance, Type 2 Diabetes, Potency Issues)

[0177] A 50-year-old man who tested positive for EBV and herpesvirus types 1 and 2, CMV, and chlamydial pneumonia had hyperinsulin resistance, elevated liver enzymes, abnormal liver metabolic function, hypercholesterolemia, hypertriglycerides, Metabolic syndrome of sleep disturbance, fatigue, poor concentration and potency problems.

[0178] In detailed EBV diagnosis, for example, a high frequency of EBNA-1+2 CISH positive B cells (50-75%) can be detected within the enriched B cell fraction of a patient. Because of this diagnosis and an unmet medical need, the patient decided to participate in compassionate use treatment with an investigational anti-EBV therapeutic vaccine, also as described in Example 2.

[0179] Cell preparations similar to Examples 1 and 2 were generated ex vivo and administered back to the patient subcutaneously (May 13, 2015).

[0180] For enhanced application, the same procedure w...

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Abstract

The present invention discloses an isolated trifunctional bispecific antibody for use in a method of treating a patient suffering from a disease and / or a disorder associated with reactivation of Epstein-Barr virus (EBV) in at least B cells and potentially also other susceptible cells such as susceptible epithelial cells, comprising: providing an autologous cell preparation of enriched B cells of said patient; incubating said enriched B cells with the trifunctional bispecific antibody for a time-period sufficient to establish a physical interaction between said trifunctional bispecific antibodyand said enriched B cells to obtain an incubation mixture; transferring said incubation mixture obtained after incubation into the same patient, wherein said trifunctional bispecific antibody comprises: (a) a first binding arm which binds to a B cell via a B cell surface antigen; (b) a second binding arm which binds to a T cell via a T cell surface antigen; (c) an Fc-portion which binds to an Fcreceptor-positive cell. The present invention also discloses a pharmaceutical composition comprising the said isolated trifunctional bispecific antibody for use in the treatment of a patient sufferingfrom a disease and / or a disorder associated with reactivation of EBV in B cells, and an ex-vivo method for preparing the said pharmaceutical composition.

Description

technical field [0001] The present invention relates to a method for treating patients suffering from diseases and / or disorders associated with reactivation of Epstein-Barr virus (EBV) in at least B cells and potentially other susceptible cells such as susceptible epithelial cells The trifunctional bispecific antibody of the method relates to a pharmaceutical composition comprising said antibody for said use, and an ex vivo method for the preparation of said pharmaceutical composition for said use. Background technique [0002] Epstein-Barr virus (EBV) is a double-stranded DNA herpes virus that causes lifelong infection in a high percentage (>90%) of the world's population. Primary infection usually occurs in childhood and is mostly asymptomatic. In developed countries, these infections are often delayed until adolescence in 50% of cases, which in some individuals produces severe symptoms that persist for years. [0003] Up to half of these delayed primary infections ar...

Claims

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Application Information

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IPC IPC(8): C07K16/28A61K39/395A61P37/04A61P3/08A61P29/00A61P17/00A61P25/28A61K39/00
CPCC07K16/2809C07K16/2887C07K2317/31A61K39/395A61K2039/505A61K2039/515A61K2039/545A61P3/08A61P17/00A61P25/28A61P29/00A61P37/04A61K39/4612A61K39/464838C12N5/0634A61K2239/31A61K39/4622C12N5/0635A61P27/02A61P43/00A61P25/02A61P3/04A61P15/02A61P19/02A61P31/14A61P3/10A61P15/00A61P11/14A61K35/14A61K35/17A61K39/3955C07K2317/14C07K2317/73C12N2501/998
Inventor 霍斯特·林德霍费尔乌苏拉·雅各布
Owner TRION RES
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