The development of drug resistance is a major problem in combating malaria caused by Plasmodium falciparum, the most deadly human malaria parasite. Resistance to artemisinin, the key component of current treatment regimens, is now being reported in parts of Asia. In this issue, Zenonos et al. report that it is possible to prevent parasite proliferation and clear a malaria infection using chimeric antibodies specific for a key host molecule required for parasite invasion of erythrocytes. Targeting a host protein rather than the parasite itself is much less likely to lead to the development of resistance, a problem that plagues treatments for virtually all infectious diseases.
In their study, Zenonos et al. generated recombinant chimeric antibodies with high affinity for the human erythrocyte surface receptor basigin. P. falciparum parasites bind to basigin as they invade erythrocytes, and this binding appears to be essential for parasite proliferation. The recombinant antibodies block this key interaction, prevent erythrocyte invasion, and thus disrupt the replicative cycle that is crucial for the maintenance of an infection. Using a humanized mouse model, the authors showed that treatment with these antibodies leads to rapid clearance of an infection with no sign of recurrence.
The strategy of targeting host proteins raises obvious concerns about toxicity and side effects of the therapy. In the case of basigin, these concerns are somewhat alleviated by previous work using anti-basigin antibodies as therapies for cancer and graft-versus-host disease, which were well tolerated. However, the authors reduced the likelihood of side effects by using chimeric antibodies that incorporated the human IgG1 and constant kappa chains, thus reducing the possibility of anti-mouse antibody responses. Further, they included an established set of mutations in the constant heavy chains that inhibit complement and Fcγ-receptor binding, thus significantly reducing the possibility of antibody effector functions targeted to the erythrocyte surface. The chimeric antibodies are therefore thought to disrupt parasite proliferation solely by blocking basigin–parasite binding.
Malaria parasites, like most infectious organisms, have demonstrated a remarkable ability to develop resistance to widely used therapies. This raises the disturbing possibility that parasites resistant to all known therapies could develop in the near future, a predicament that is now confronting the tuberculosis community. By expanding our list of potential targets for disease intervention to several key host molecules—the first time this has been successfully demonstrated for malaria—we can potentially create new therapies that are less vulnerable to the rapid generation of resistance.