Abstract
Various CD7-targeting immunotoxins have been tested for its potential in treating CD7+ malignant patients but none of those immunotoxins was approved clinically because of lacking enough efficacy and safety. Here we successfully constructed the monovalent and bivalent CD7 nanobody-based immunotoxins PG001 and PG002, both conjugated with a truncated derivative of Pseudomonas exotoxin A respectively. The prokaryotic system expressed immunotoxins not only maintained their binding specificity for CD7-positive cells with a Kd of 16.74 nM and 3.6 nM for PG001 and PG002 respectively, but also efficiently promoted antigen-restricted apoptosis of the CD7-positive leukemia cell lines Jurkat and CEM, and primary T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) cells with an in vitro cytotoxic activity (EC50) in the range of 23-30 pM for PG002. In NOD/SCID mice transplanted with CEM cells, PG001 and PG002 prevented engraftment of the cells and markedly prolonged mouse survival. Owing to the efficient antigen-restricted anti-leukemic activity of PG002, this CD7 nanobody-based immunotoxin exhibited a superior anti-CD7 positive malignancies activity than previously reported immunotoxins, and may represent a promising therapeutic strategy in treating CD7-positive leukemia and lymphoma, which still remain a significant clinical challenge.
Highlights
T-cell lymphomas and leukemias are heterogeneous hematological malignancies
We further examined the specificity of VHH6 for CD7 using flow cytometric and immunofluorescence assays
We identified a nanobody against CD7, VHH6, with high affinity and specificity, and constructed the monovalent and bivalent VHH6-based immunotoxins PG001 and PG002 respectively
Summary
T-cell lymphomas and leukemias are heterogeneous hematological malignancies. conventional therapeutic strategies for aggressive adult T-cell leukemialymphoma (ATL) are not associated with satisfactory outcomes, mainly because ATL cells are often resistant to chemotherapeutic agents [1]. ATL treatment efforts, including allogeneic hematopoietic stem cell transplantation and molecularly targeted therapies [2, 3], have improved overall survival durations. Treatment with the monoclonal anti-CCR4 antibody mogamulizumab produced marked cytotoxic effects on ATL cells, especially leukemic ATL cells [4]. Once a patient experiences chemoresistance or a relapse, treatment options are limited, and the survival duration is short. Effective novel therapies with distinctive mechanisms that can avoid multi-drug resistance and have favorable specificity and toxicity profiles are needed to treat human T-cell malignancies. Recent findings indicated that immunotoxins have highly and cytotoxic effects on tumor cells in vitro and in vivo, which may represent an important method of cancer therapy [7, 8]
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