Advances in anticancer immunotoxin therapy

Abstract

Immunotoxins are a novel class of antibody-conjugated therapeutics currently in clinical development for a variety of malignancies. They consist of an antibody-based targeting domain fused to a bacterial toxin payload for cell killing. Immunotoxins kill cells by inhibiting protein synthesis, a unique mechanism of action that is toxic to both dividing and nondividing cells. Recent advances in the design and administration of immunotoxins are overcoming historical challenges in the field, leading to renewed interest in these therapeutics.

Keywords: Antibody conjugate; Antidrug antibody; Recombinant immunotoxin; Vascular leak syndrome.

Figure 1.

Structure of select toxins and immunotoxins. Native Pseudomonas exotoxin A contains three domains: domain I (binding), domain II (unknown function), and domain III (catalytic domain). In the SS1P immunotoxin, domain I is replaced by a double-stranded Fv (V_L and V_H) that targets mesothelin. The engineered disulfide bond links V_L and V_H. The RG7787 immunotoxin uses a humanized Fab fragment and lacks PE domain II. Diphtheria toxin also contains three domains: catalytic, transmembrane, and binding. In denileukin diftitox, the B domain is replaced by human IL-2 to permit binding to cells bearing the IL-2 receptor. Gelonin is a plant toxin with n-glycosidase activity that inhibits ribosomal activity to halt protein synthesis. It consists of a single domain. In the hSGZ immunotoxin, recombinant gelonin is fused to a single-chain Fv (V_L and V_H) that binds fibroblast growth factor receptor 14-kDa protein (Fn14), and a bZIP domain that increases activity of the immunotoxin by allowing dimerization. Abbreviations: A, catalytic domain; B, binding domain; Gel, gelonin; IL-2, interleukin-2; rGel, recombinant gelonin; T, transmembrane domain.

Figure 2.

Delivery of ADCs and immunotoxins. ADCs and immunotoxins bind to partners (HER-2, MSLN, or IL-R) on the cell surface and are internalized into an endocytic compartment. The ADC ado-trastuzumab maytansine traffics to lysosomes, where the maytansine chemotherapeutic is released from the antibody structure, allowing drug penetration into the cytosol, disruption of microtubule dynamics, and cell death (left). In endosomes, the modified PE toxin is cleaved from SS1P by the furin protease (middle). PE then undergoes retrograde transport through the Golgi to the endoplasmic reticulum. The method for egress from the endoplasmic reticulum to the cytosol is unknown. The toxin catalyzes irreversible ADP ribosylation of eEF2, leading to global inhibition of protein synthesis and cell death. The T domain (Fig. 1) of DT forms a pore in the membrane of the endosome, allowing transit of DT into the cytoplasm (right). Like PE, DT also catalyzes inhibitory modification of eEF2. Abbreviations: ADC, antibody-drug conjugate; ADP-ribose, adensodine diphosphate ribose; DT, diphtheria toxin; eEF2, eukaryotic elongation factor 2; IL-2, interleukin-2; IL-R, interleukin-2 receptor; MSLN, mesothelin; PE, Pseudomonas exotoxin A.

Figure 3.

Durable response with SS1P plus lymphocyte-depleting regimen. Coronal computed tomography images of a responding patient 12 days after initiation of therapy on an SS1P, pentostatin, and cyclophosphamide clinical trial with durable response continuing at 24 months, more than 16 months after the last treatment.