Recombinant Immunotoxins for the Treatment of Chemoresistant Hematologic Malignancies

Abstract

Recombinant immunotoxins are proteins composed of fragments of monoclonal antibodies fused to truncated protein toxins. No agents of this class are approved yet for medical use, although a related molecule, denileukin diftitox, composed of interleukin-2 fused to truncated diphtheria toxin, is approved for relapsed/refractory cutaneous T-cell lymphoma. Recombinant immunotoxins which have been tested in patients with chemotherapy-pretreated hematologic malignancies include LMB-2 (anti-CD25), BL22 (CAT-3888, anti-CD22) and HA22 (CAT-8015, anti-CD22), each containing an Fv fragment fused to truncated Pseudomonas exotoxin. Major responses were observed with LMB-2 in adult T-cell leukemia, chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma, Hodgkin's disease, and hairy cell leukemia (HCL). BL22 resulted in a high complete remission rate in patients with HCL, particularly those without excessive tumor burden. HA22, an improved version of BL22 with higher affinity to CD22, is now undergoing phase I testing in HCL, CLL, non-Hodgkin's lymphoma, and pediatric acute lymphoblastic leukemia.

Epidermal growth factor receptor is overexpressed in neuroblastoma tissues and cells

“…Finally, the absorbance in each well was measured at 450 nm with a microplate reader (Thermo, Waltham, USA). A431 cell, a human epidermoid squamous cell carcinoma cell line, which over-expresses EGFR on the cell membrane [11], was used as the positive control [16]. HFL1 cell, a human normal fibroblast lung cell line, was used as the control group [17].…”

“…In particular, a recombinant IT protein composed of a diphtheria toxin fragment and interleukin-2 fusion protein has been used to treat lymphoma [9,10]. Similarly, a recombinant IT fused with anti-CD22 monoclonal antibody and pseudomonas exotoxin segment has been successfully used in the treatment of hairy cell leukemia, with the complete remission rate of 60% [11]. Thus, for some refractory tumors, IT therapy can be a promising strategy.…”

Pseudomonas aeruginosa exotoxin T induces potent cytotoxicity against a variety of murine and human cancer cell lines

“…Bacterial toxins have been, and continue to be, evaluated in various clinical trials as potential cancer therapeutics (Kawakami et al, 2006;Kreitman, 2006Kreitman, , 2009. For example, Pseudomonas exotoxin A and diphtheria toxin are the most common bacterial toxins that have been or are currently under clinical evaluation against a variety of haematologic malignancies and solid tumours with promising results (reviewed by Becker & Benhar, 2012).…”

Improving the Therapeutic Potential of Human Granzyme B for Targeted Cancer Therapy

“…First-generation ITs have shown promising results in in vitro studies and preclinical tests [18][19][20][21][22][23][24][25][26][27][28] and have also been tested in a small number of clinical trials [29,30]. The most prominent example is a recombinant IT comprising the diphtheria toxin and interleukin-2, which has been approved by the FDA for the treatment of T-cell lymphoma [31].…”