Antibody fusion proteins: anti-CD22 recombinant immunotoxin moxetumomab pasudotox

Area of Science:

• Oncology
• Immunotherapy
• Molecular Biology

Background:

• Recombinant immunotoxins combine antibody fragments (Fv) with cytotoxic protein domains (e.g., Pseudomonas exotoxin A [PE38]) to target cancer cells.
• Moxetumomab pasudotox is an advanced immunotoxin targeting CD22, an antigen present on B-cell malignancies.
• Previous immunotoxin BL22 showed efficacy in hairy cell leukemia (HCL) but limited response in chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL) due to lower CD22 expression.

Purpose of the Study:

• To evaluate the enhanced efficacy and safety of moxetumomab pasudotox compared to BL22 in B-cell malignancies.
• To explore the therapeutic potential of moxetumomab pasudotox in hairy cell leukemia (HCL), chronic lymphocytic leukemia (CLL), B-cell lymphomas, and acute lymphoblastic leukemia (ALL).

Main Methods:

• Moxetumomab pasudotox, a fusion protein of anti-CD22 Fv and PE38, was engineered for increased potency.
• In vitro studies assessed activity against lymphoma cell lines and patient-derived leukemic cells.
• Phase I clinical trials were conducted in patients with HCL, CLL, B-cell lymphomas, and childhood ALL.

Main Results:

• Moxetumomab pasudotox demonstrated up to 50-fold greater activity than BL22 against relevant cell lines and patient samples.
• A Phase I trial in HCL patients yielded response rates comparable to BL22 but without dose-limiting toxicities.
• Ongoing Phase I trials are evaluating moxetumomab pasudotox in CLL, B-cell lymphomas, and childhood ALL.

Conclusions:

• Moxetumomab pasudotox represents a more potent and potentially safer immunotoxin for treating CD22-expressing B-cell malignancies.
• Further clinical development is warranted for HCL, CLL, B-cell lymphomas, and ALL.
• Ongoing protein engineering aims to further enhance efficacy and minimize off-target effects.