Next-generation monoclonal antibody prevents malaria

In a recent study published in The New England Journal of Medicine, researchers investigate the pharmacokinetics and safety of L9LS, a monoclonal antibody (mAb) to prevent malaria.

Study: Low-Dose Subcutaneous or Intravenous Monoclonal Antibody to Prevent Malaria. Image Credit: Kateryna Kon /


Malaria is a mosquito-borne disease caused by Plasmodium parasites. Sub-Saharan Africa bears a disproportionate burden of malaria, with deaths among children aged five or younger accounting for 80% of malaria-associated deaths in this region.

Although the World Health Organization (WHO) has recommended the Mosquirix (RTS, S/AS01) vaccine for widespread use in infants, it is only partially protective, with a reported efficacy of 36.3%.

Despite the progress in vaccine development, there remains an urgent need for additional strategies to reduce the incidence of malaria and its associated mortality. Reports suggest that mAbs prevent malaria by P. falciparum at the pre-erythrocytic stage by binding to the parasite’s circumsporozoite protein (CSP), thereby neutralizing infecting sporozoites. It has also been speculated that anti-CSP mAbs could be broadly protective against circulating parasite strains.  

Previously, researchers determined the safety and effectiveness of a potent mAb, CIS43LS, that targets the junctional region of the P. falciparum CSP. To this end, CIS43LS conferred protection against malaria to participants after intravenous dosing, followed by controlled infection. No safety concerns were identified.

Improving the potency and lowering the volume of mAbs are critical to limit costs and allow for their subcutaneous administration.

About the study

In the present study, researchers evaluate the safety, efficacy, and pharmacokinetics of L9LS, a next-generation mAb, in Phase I clinical trial.

The primary objectives were to assess the safety and side-effect profiles of L9LS. The secondary objectives included pharmacokinetic and efficacy analysis after a controlled infection with the malarial parasite two to six weeks post-administration of the mAb.

L9LS, a human immunoglobulin G1 (IgG1) mAb, was administered intravenously at a dose of 1, 5, or 20 mg/kg of body weight. Those administered subcutaneously received a dose of 5 mg/kg in one or two injections.

Any adverse events were recorded for four weeks after mAb administration and controlled infection. Serious adverse events and new medical conditions were recorded throughout the trial.

Participants were exposed to Anopheles stephensi mosquitoes infected with P. falciparum for controlled malaria infection. Patients were then contacted twice in the first week and received follow-up care during in-clinic visits until 17 days post-infection (dpi).

At 21 dpi, parasitemia was assessed by performing a polymerase chain reaction (PCR) test. Participants were considered to be protected if no parasitemia was evident. Standard treatment was initiated for all subjects upon detection of parasitemia or from 21 dpi for three consecutive days.

Study findings

Twenty-seven individuals were enrolled in the trial, 18 of whom received the antibody and nine who did not receive L9LS and served as controls.

Twenty-three subjects, which consisted of 17 L9LS recipients and six controls, underwent controlled malarial infection. Ten participants were challenged within four weeks of L9LS administration and seven after five to six weeks.

No serious adverse events or infusion-related reactions were recorded. One L9LS recipient experienced mild cervical lymphadenopathy after nine days, which was attributed to L9LS administration; however, it was resolved by 29 days without intervention. Pharmacokinetic assessments were performed in all mAb recipients with at least eight weeks of data.

The highest average maximum serum concentration (Cmax) of L9LS was 914.2 μg/ml in those who received the 20 mg/kg dose intravenously. The lowest mean Cmax was 41.5 μg among those with 1 mg/kg intravenous dosing.

The mean Cmax was 164 μg among the recipients of an intravenous dose of 5 mg/kg and 68.9 μg for those with a subcutaneous dose of 5 mg/kg.

The time of maximum concentration (Tmax) occurred six days after subcutaneous injection, with serum concentrations exceeding 10 μg/ml within one day post-subcutaneous administration. The overall clearance rate was 46.1 ml/day, the half-life was 56 days, the volume of distribution was 3.67 liters, and the subcutaneous bioavailability was 69%.

Parasitemia developed in two L9LS recipients and all controls. One of the L9LS recipients received 1 mg/kg L9LS intravenously, whereas the other received 5 mg/kg subcutaneously. Parasitemia was not detected in any subject who received 5 or 20 mg/kg intravenously.


L9LS was protective against controlled infection in this small trial with no safety concerns. A favorable safety profile was recorded, with no infusion-related reactions reported after intravenous injection.

Subcutaneous administration also had a similar safety profile with mild/moderate reactogenicity that resolved shortly after L9LS administration. The estimated half-life of 56 days indicated that the protection against malaria was sustained.

Protection against infection occurred even at a low serum concentration of 9.2 μg/ml. Notably, pharmacokinetic modeling indicated that participants who received 5 mg/kg subcutaneously would retain 5-11 μg/ml of L9LS in circulation at six months.

Overall, the current trial showed that a next-generation mAb could prevent malaria. Further investigations are required to define the potential of the subcutaneous regimen of a single low dose of L9LS.

Journal reference:

  • Wu, R. L., Idris, A. H., Berkowitz, N. M., et al. (2022). Low-Dose Subcutaneous or Intravenous Monoclonal Antibody to Prevent Malaria. The New England Journal of Medicine 387;397-407. doi:10.1056/NEJMoa2203067.