Next Generation Antimalarial MAB Targets Susceptibility of P falciparum

A next generation antimalarial monoclonal antibody (MAB) demonstrated three times the potency of its predecessor in preventing parasitemia by targeting P falciparum sporozoites injected by mosquito before they can replicate, in a phase 1 trial that determined safe and efficacious dosage, and minimum effective serum concentration.

Richard Wu, MD, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, and colleagues noted the recent development of an antimalarial vaccine, and explained the separate pursuit of passive immune protection from an MAB.

"Passive administration of monoclonal antibodies can consistently provide a defined concentration at a protective titer," Wu and colleagues wrote. "This approach differs from vaccines that may have variable immune priming and can be influenced by previous exposure to malaria, age, and immunocompetence, which can vary across persons."

In a concurrently published "Science Behind the Study" article, Timothy Wells, ScD, and Cristina Donini, PharmD, PhD, Medicines for Malaria Venture, Geneva, Switzerland, explain that the circulating antibodies from this investigational MAB, L9LS, persist after administration, and find the relatively small number of sporozoites in the blood within minutes after they are introduced by the mosquito. The sporozoites are inactivated before they can infiltrate and replicate in the liver (to then rupture out of the hepatocytes as several trillion merozoites, which would cyclically invade and rupture red blood cells with accompanying cycles of fever).

L9LS targets a highly conserved epitope of the circumsporozoite protein 1 (CSP-1), the predominant protein of the sporozoite, and its means for adhesion to human hepatocytes. Wells and Donini point out that eradication is more likely with fewer organisms, and that such efficacy also reduces the opportunity for the organism to develop resistance to the intervention.

An additional strength of L9LS is its incorporation of an LS mutation that increases neonatal Fe receptor binding; and, as that system facilitates the transfer and extending of passive immunization from mother to infant, so does it extend the active half life of the MAB in the blood (from 21 days of the prior generation MAB product, CIS43LS, to 56 days).The resulting activity over 3 to 6 months potentially provides protection for children and other vulnerable populations from one injection per season.

In the phase 1 trial, Wu and colleagues recruited 27 healthy adult participants to undergo controlled malaria infection within 2 to 6 weeks of receiving L9LS either intravenously or subcutaneously at a dose of 1, 5, or 20mg/kg; or as placebo in 6 participants. Clinic assessments for parasitemia were conducted through day 21 after exposure. Standard treatment of 1gm atovaquone and 400mg proguanil hydrochloride for 3 consecutive days was provided on confirmation of parasitemia, or on day 21 if not previously treated. All participants were followed for 24 weeks after receiving L9LS.

The investigators reported that of the 17 participants who received a single dose of L9LS, 15 (88%) were protected from infection. Parasitemia did not develop in any of the participants who received 5 or 20mg/kg intravenously. Parasitemia did develop in 1 of 5 participants receiving 1mg/kg intravenously, and in 1 of 5 who received 5mg/kg subcutaneously. All 6 control participants manifested parasitemia within 21 days after the controlled infection. Protection from L9LS was found to be conferred at serum concentrations as low as 9.2μg/ml; and the serum concentrations from subcutaneous administration, albeit lower, were similar to those with intravenous administration.

Wu and colleagues anticipate that L9LS will be useful in the field, particularly with the demonstration of therapeutic levels and effective protection from subcutaneous administration. They also indicated that there were no evident safety concerns.

"Administration of a single subcutaneous dose of a monoclonal antibody at the beginning of the transmission season could provide protection, overcome adherence issues, and potentially limit the emergence of drug-resistant strains associated with long-term use of seasonal malaria chemoprevention," Wu and colleagues wrote.

In an accompanying editorial, Johanna Daily, MD, Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, emphasized the major strength of MAB therapy, providing reliable level of antibody regardless of the host immune status.

"Monoclonal antibodies against malaria may have a distinct role in rapidly controlling infection in areas where there are malaria outbreaks, in locations where antimalarial drug resistance is emerging, and in persons who are unable to mount a protective antibody response to vaccines," he wrote.

Daily cautioned that the development of treatment resistance remains possible with any intervention, but envisioned how this might be overcome with future vaccines and cross-reactive MABs targeting multiple antigens. "It is hoped that the L9LS monoclonal antibody will become a potential weapon to accelerate the battle for control and global eradication of malaria," Daily indicated.