Herceptin is thought to act by blocking the binding of the natural ligand (so far unidentified) to this receptor, and by downregulating the level of expression of the receptor. The effects of this antibody can be enhanced when it is combined with conventional chemotherapy. Beyond blocking a growth signal for tumor cells, experiments in mice suggest that some of trastuzumab’s antitumor effects also involve innate and adaptive immune responses, such as directing ADCC or inducing antitumor T-cell responses. A monoclonal antibody that has yielded excellent results in the treatment of non-Hodgkin’s B-cell lymphoma is the anti-CD20 antibody rituximab, which triggers the apoptosis of B cells upon binding to CD20 on their surface (see Section 16-7). ADCC may be another mechanism by which rituximab acts, as its clinical efficacy has been linked to polymorphisms in activating Fc receptors.
Technical problems with monoclonal antibodies as therapeutic agents include inefficient killing of cells after binding the monoclonal antibody, inefficient penetration of the antibody into the tumor mass (which can be improved by using small antibody fragments), and soluble target antigens mopping up the antibody. The efficiency of killing can be enhanced by linking the antibody to a toxin, producing a reagent called an immunotoxin (see Fig. 16.19): two favored toxins are ricin A chain and Pseudomonas toxin. The antibody must be internalized to allow cleavage of the toxin from the antibody in the endocytic compartment, permitting the freed toxin chain to penetrate and kill the cell. Toxins coupled to native antibodies have had limited success in cancer therapy, but fragments of antibodies such as single-chain Fv molecules (see Section 4-3) show more promise. An example of a successful immunotoxin is a recombinant Fv anti-CD22 antibody fused to a fragment of Pseudomonas toxin, which induced complete remissions in two-thirds of a group of patients with a type of B-cell leukemia known as hairy-cell leukemia in whom the disease was resistant to conventional chemotherapy.
Monoclonal antibodies can also be conjugated to chemotherapeutic drugs or to radioisotopes. In the case of a drug-linked antibody, the binding of the antibody to a cell-surface antigen concentrates the drug to the site of the tumor. After internalization, the drug is released in the endosomes and exerts its cytostatic or cytotoxic effect. For example, the antibody trastuzumab has been linked to the cytotoxic agent mertansine, a drug that inhibits the assembly of microtubules, in a conjugate called T-DM1. Since HER-2 is overexpressed only in cancer cells, T-DM1 selectively delivers the toxin specifically to tumor cells.