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TRIFECTA - Development of a novel trispecific antibody for the anticancer immune targeting of non-Hodgkin Lymphoma
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Resumo(s)
Non-Hodgkin Lymphoma (NHL) is among leading causes of cancer-related death
worldwide, although prognosis has improved in recent years. Several innovative drugs are in
clinical development for NHL treatment; however, approvals remain limited, partly due to the
lack of clinically relevant models for validation. Immunotherapy strategies have been developed;
however, the high pace of clinical application present challenges, highlighting the need for novel
strategies and models for developing successful and cost-effective immunotherapies. Due to its
similarity to human disease, the canine lymphoma model has been suggested as a powerful tool
for translating novel immunotherapies into clinical practice. A promising approach to optimize
immunotherapy involves the development of bispecific antibodies that simultaneously bind to
cancer cells and recruit T-lymphocytes, redirecting and unleashing T-lymphocytes cytotoxicity
against cancer cells. However, by engaging the TCR/CD3 complex alone, most bispecific
antibodies lead to T-lymphocytes activation and faster exhaustion. This project aimed to develop
a trispecific antibody (TsAb) targeting CD20 receptor, overexpressed in B-lymphocytes
malignancies, and CD3 and CD28 receptors on T-lymphocytes. Targeting CD3 activates Tlymphocytes, while targeting CD28 supports long-lasting T-lymphocytes proliferation by
supplying a co-stimulatory signal that activates an alternate signal transduction pathway and
inhibits apoptosis. For that purpose, TsAb targeting canine CD20, CD3, and CD28 was
engineered, produced, and purified. Optimization of canine T-lymphocyte isolation was
conducted for in vitro assays evaluating TsAb’s ability to promote T- lymphocyte activation and
canine NHL cell cytotoxicity. A Phage Display selection was carried out on a rabbit single domain
(sdAb) antibody library, identifying antibodies specific to canine CD3. ELISA screening allowed
the selection of sdAbs with promising expression and binding properties, which could be
integrated into improved TsAb in the future. Overall, this project supports the development of
next-generation T- lymphocytes engager antibodies for cancer treatment, while providing realistic
opportunities for clinical translation.
Descrição
Tese de mestrado, Biologia Molecular e Genética , 2025, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Linfoma Imunoterapia Anticorpo Triespecífico Phage Display CD3 Teses de mestrado - 2025