Novel CD7-specific nanobody-based immunotoxins potently enhanced apoptosis of CD7-positive malignant cells

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• CD7-targeting immunotoxins have shown potential for CD7+ malignancies but lacked clinical approval due to insufficient efficacy and safety.
• Existing treatments for CD7-positive leukemias and lymphomas present significant clinical challenges.

Purpose of the Study:

• To construct and evaluate novel monovalent and bivalent CD7 nanobody-based immunotoxins, PG001 and PG002.
• To assess the efficacy and safety of these immunotoxins in preclinical models of CD7-positive malignancies.

Main Methods:

• Construction of monovalent (PG001) and bivalent (PG002) CD7 nanobody-based immunotoxins conjugated with a truncated Pseudomonas exotoxin A derivative.
• Evaluation of binding specificity and affinity (Kd) to CD7-positive cells.
• Assessment of in vitro cytotoxic activity (EC50) against leukemia cell lines (Jurkat, CEM) and primary T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) cells.
• In vivo efficacy studies in NOD/SCID mice xenografted with CEM cells.

Main Results:

• Both PG001 and PG002 demonstrated specific binding to CD7-positive cells with high affinity (Kd: 16.74 nM for PG001, 3.6 nM for PG002).
• PG002 exhibited potent antigen-restricted apoptosis induction and cytotoxic activity (EC50: 23-30 pM) against various CD7-positive leukemia cells.
• In vivo studies showed that PG001 and PG002 prevented tumor engraftment and significantly prolonged survival in mice.

Conclusions:

• The developed CD7 nanobody-based immunotoxins, particularly PG002, display superior anti-leukemic activity compared to previously reported immunotoxins.
• These novel immunotoxins represent a promising therapeutic strategy for treating challenging CD7-positive leukemias and lymphomas.