An antibody-drug conjugate with intracellular drug release properties showing specific cytotoxicity against CD7-positive cells
| Autor: | Daniel J. Williamson, Sabine Milhas, Jing Zhang, Majid Al Nakeeb, Jenny Thirlway, Adam Lodge, Arvind K. Jain, Ami Miller, Terry Rabbitts, Justyna Helena Mysliwy |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Cancer Research Antibody-drug conjugate Immunoconjugates Lung Neoplasms T cell Cell Mice Nude Apoptosis Antigens CD7 Jurkat cells Article 03 medical and health sciences Mice 0302 clinical medicine Antigen Intracellular drug delivery hemic and lymphatic diseases medicine Tumor Cells Cultured Cytotoxic T cell Animals Humans Leukaemia Antibody Cell Proliferation biology Chemistry Antibodies Monoclonal CD7 Hematology Xenograft Model Antitumor Assays body regions Drug Liberation medicine.anatomical_structure Cell killing Oncology ADC T cell leukaemia 030220 oncology & carcinogenesis biology.protein Cancer research 030215 immunology |
| Zdroj: | Leukemia Research |
| ISSN: | 1873-5835 |
| Popis: | Highlights • The CD7 surface protein is highly expressed on T cell acute leukaemias. • CD7 bound by antibody is rapidly processed and internalised into cells. • The novel antibody-drug conjugate kills CD7 expressing leukaemias. • The ADC linker is only cleaved in cells. • CD7 ADCs are a treatment option for CD7-expressing cancers. Refractory T cell acute leukaemias that no longer respond to treatment would benefit from new modalities that target T cell-specific surface proteins. T cell associated surface proteins (the surfaceome) offer possible therapy targets to reduce tumour burden but also target the leukaemia-initiating cells from which tumours recur. Recent studies of the T cell leukaemia surfaceome confirmed that CD7 is highly expressed in overt disease. We have used an anti-CD7 antibody drug conjugate (ADC) to show that the binding of antibody to surface CD7 protein results in rapid internalization of the antigen together with the ADC. As a consequence, cell killing was observed via induction of apoptosis and was dependent on cell surface CD7. The in vitro cytotoxic activity (EC50) of the anti-CD7 ADC on T cell acute leukaemia (T-ALL) cells Jurkat and KOPT-K1 was found to be in the range of 5−8 ng/mL. In a pre-clinical xenograft model of human tumour growth expressing CD7 antigen, growth was curtailed by a single dose of ADC. The data indicate that CD7 targeting ADCs may be developed into an important second stage therapy for T cell acute leukaemia, for refractory CD7-positive leukaemias and for subsets of acute myeloid leukaemia (AML) expressing CD7. |
| Databáze: | OpenAIRE |
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