Свързващи и неутрализиращи антитела срещу интерферон-бета при лечение на множествена склероза
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Дата
2017-01-16
Автори
Христова-Чакмакова/Hristova-Chakmakova, Соня Иванова/Sonya Ivanova
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ЦЕЛ И ЗАДАЧИ:
Настоящият дисертационен труд си поставя за цел да определи клиничното значение на неутрализиращите антитела и ролята им в избора на терапия. ***
За постигането на посочената цел са формулирани следните задачи:
1. Изследване на терапевтичния ефект на IFNβ при пристъпна МС чрез използване на клинични критерии за оценка:
- Годишна честота на пристъпите (Annualised relapse rate, ARR);
- Установяване на трайно акумулиране на инвалидизация (Sustained Accumulation of Disability) след иницииране на терапи-ята с IFNβ – дефинирано като увеличение на оценката по скала-та EDSS с ≥ 1.0, което се задържа за период от 6 месеца;
- Процент на „свободни от пристъпи“;
- Процент на „свободни от трайно акумулиране на инвалидизация“;
- Процент на пациентите, които са „напълно клинично стабилни“;
- Определяне на тежестта на пристъпа (първи и втори след за-почване на лечението);
- Определяне на времето до първи и между първи и втори пристъп.
2. Изследване на имуногеността на интерфероновите медикаменти чрез двустъпков метод на имуноанализ.
3. Проучване на наличието на връзка между терапевтичния ефект от прилагания IFNβ и BAb/NAb статуса.
4. Изследване на серопозитивността при пациенти в юношеска възраст.
5. Търсене на разлики в серопозитивните и серонегативните групи (търсене на биологична предиспозиция за образуване на неутра-лизиращи антитела).
6. Анализ на допускането, че NAb инхибират и ендогенния интер-ферон-бета.
7. Изследване на влиянието на тютюнопушенето върху образуване-то на антитела срещу IFNβ.
8. Определяне на приложимостта в клиничната практика на BAb и NAb в алгоритъм при мониториране на лечението с интерферон-бета. ***** SUMMARY *****
Even though interferon-beta (IFNβ) treatment shows beneficial clinical effects, especially started at an early stage of multiple sclerosis (MS), it is associated with the development of anti-drug antibodies (ADAs). Neutralizing antibodies at high titer levels reduces drug efficacy. It is unknown why only a subgroup of treated MS patients develops ADAs.
The aim of this study was to determine the frequency of IFNβ binding (BAbs) and neutralizing antibodies (NAbs) against different formulation of IFNβ in the treatment of multiple sclerosis and to assess the clinical impact of antibody status.
Three hundred fifty-eight subjects took part in the study – 201 treated with IFNβ-1a, and 157 with IFNβ-1b. Separately, a group of 11 adolescents was investigated. Binding antibodies were detected by ELISA and neutralizing by gene reporter luciferase assay.
In our study seroprevalence of BAb is 45.8 %. Among the BAb(+) 28.2% were NAb seropositive. The overall frequency of NAb-positive patients in our adult cochort is 12.8%. IFNβ-1b preparation are more immunogenic than IFNβ-1a.
In addition to the annual relapse rate and EDSS scoring, we studied the severi-ty of the first and the second relapse after the beginning of treatment as well as the time to first and between the first and the second attack as clinical parame-ters of efficacy
We hypothesized that MS patients with and without autoimmune comorbidity have different propensities to induce humoral immune responses. We did not find that the presence of other autoimmune conditions is associated with Nab development. We did not find any likely possible relationship between sero-logical status and family history of multiple sclerosis.
Because of the notion that NAbs may affect not only exogenous, but also the naturally occurring IFN, we searched for incidence of osteoporosis, cancer and frequency of viral infections. There are no differences between seropositive and seronegative groups.
Applying ROC analysis we aimed to answer whether BAb titer can be used to predict NAb positivity and the treatment response respectively.
We analyzed if presence of ADA is associated with generalized and local side effect of IFNβ. Because of inversely proportional relation we conclude that the lack of generalized side effects can be used to predict patients at risk of becoming antibody positive. For such patients we recommend earlier NAb test-ing than the others.
We try to investigate cigarette smoking as factor influence the development of ADA in MS patients. Smoking may contribute to the induction of anti drug antibodies against IFNβ.
We observed a small group with NAb titer. The majority of them had high titer; even the only patient, treated with IFNβ-1a, also had a high titre. Because of that result we do not suggest MS patient, treated with less immunogenic IFNβ-1a i.m. to be excluded from ADA screening.
Importantly in adolescent age we found higher rate of seropositivity even though it is not statistically significant because of the small number of patients.
In conclusion, a systematic immuno-clinical investigation of anti interferon-beta antibodies development and their clinical impact was performed in a huge group of multiple sclerosis patients for the first time in Bulgaria. Various im-portant conclusions and clinical contributions were achieved. Overall, these results can be used to assist when making decisions about whether treatment should be changed or not. In addition, the identification of factors contributing to the immunogenicity of protein therapeutics can increase our understanding of the immunological mechanisms leading to ADA responses, possibly result-ing in less immunogenic drugs in the future.
Описание
Дисертационен труд за присъждане на образователна и научна степен "Доктор" /CD/ / Соня Иванова Христова-Чакмакова . - София, 2016 . - 234 с. + Автореферат /CD/ - НАУЧНА СПЕЦИАЛНОСТ „НЕВРОЛОГИЯ“
НАУЧЕН РЪКОВОДИТЕЛ: АКАД. ПРОФ. Д-Р ИВАН МИЛАНОВ, Д.М.Н.; СОФИЯ - 2016
Ключови думи
Нервна система - болести – дисертации; Имунна система - болести – дисертации; Антитела – дисертации; Интерферон - бета – дисертации; Мултиплена склероза – дисертации , Nervous System Diseases – dissertations; Immune System Diseases – dissertations; Antibodies – dissetations; Interferon-beta – dissertations; Multiple Sclerosis - dissertations