Today, malaria is still a global health problem. Despite major epidemiological studies being carried out, it still kills millions of people every year, mostly in sub-Saharan Africa. Research for the development of new, more effective drugs has led to a long list of treatments, from traditional remedies to sophisticated pharmaceutical interventions over the last decades. Recent novel drugs are monoclonal antibody (mAb) therapies, which prove promising and worth covering in this article, which will explore the evolution of monoclonal antibodies in the treatment of malaria, the present vision, and possible future improvements and innovations.
Understanding Monoclonal Antibodies
In this context, researchers use monoclonal antibodies, produced by cloning a single type of immune cell to generate billions of identical antibodies that recognize the same antigen. Scientists have engineered these monoclonal antibodies to specifically target components of the malarial Plasmodium parasites.
Historical Context: From Traditional to Modern Treatments
Traditional Malaria Treatments
For centuries, when patients suffered from malaria or chronic remittent malaria before modern medicine became available, they received various traditional plant and herbal remedies. Early in the 17th century, one of those treatments, quinine from the bark of the cinchona tree, would be the first of a series of antimalarial treatments that were not medicinal cocktails. Since then, synthetic antimalarial drugs such as chloroquine and artemisinin, and their derivatives, have also brought enormous improvements in the treatment of malaria.
Advances in Antimalarial Drugs
It was the development of the artemisinin-based combination therapies, or ACTs, that represented an enormous advance in malaria treatment. ACTs include artemisinin derivatives in combination with other available antimalarial drugs such as the older mefloquine (Lariam), known to be safe and effective, to improve drug efficacy and reduce the chances of resistance becoming established. ACTs are now the standard for treating uncomplicated Plasmodium falciparum malaria.
The Emergence of Monoclonal Antibodies
Initial Research and Development
Taking advantage of new techniques to produce monoclonal antibodies on a large scale, the idea of treating infectious diseases with monoclonal antibodies picked up steam in the late 20th century. Monoclonal antibodies can bind specifically to a certain kind of antigen on the surface of the pathogen, potentially offering a targeted treatment option for infectious diseases. The first studies focused on finding monoclonal antibodies against various kinds of infectious agents, including malaria.
Targeting Plasmodium Parasites
In the case of malaria, monoclonal antibodies against multiple targets across the lifecycle have been engineered, including:
- Surface Antigens: Antibodies directed at surface proteins on Plasmodium parasites, such as those expressed by the merozoites that invade red blood cells.
- Exoantigens: antibodies against proteins produced by the parasite in the liver or during early infection.
- Vaccine Candidates: Monoclonal antibodies are used for the design of vaccines in which the monoclonal antibody helps to identify and target antigens that trigger an immune response.
Key Monoclonal Antibody Therapies in Development
Cizolfigo (formerly known as GMZ2)
This is a monoclonal antibody therapy against Plasmodium falciparum that disrupts the parasites’ attachment to red blood cells, thus preventing infection. Cizolfigo has shown efficacy in reducing parasite load and improving symptoms in patients with malaria in phase 2 clinical trials.
Cis-9D3
This monoclonal antibody acts against the liver stage of the parasite Plasmodium vivax, blocking its transmission into and replication in liver cells, thereby preventing the disease relapse and decreasing the burden of malaria caused by P vivax.
AMA1-targeted Monoclonal Antibodies
AMA1 (for apical membrane antigen 1) is a parasite protein necessary for the red blood cell invasion that initiates malaria. In preclinical models, using monoclonal antibodies to target AMA1 has decreased parasite invasion and improved treatment.
RTS, S/AS01 (Mosquirix)
Although it’s not a monoclonal antibody, I would be remiss not to mention the RTS, S/AS01 vaccine that was developed for use against malaria. This was the first vaccine for a major parasite disease to gain an endorsement from the WHO, and it has shown efficacy in protecting against Plasmodium falciparum. Because monoclonal antibody studies often identify potential vaccine targets, efforts to develop vaccines and monoclonal antibodies go hand in hand, expanding the range of therapeutics available to combat these diseases.
Clinical Trials and Evidence
Preclinical Studies
Preclinical studies could, for example, elucidate which mAb targets Plasmodium parasites most effectively. This can be done by studying animal models to evaluate the safety, efficacy, and side-effects of mAb therapies further before proceeding to human trials.
Clinical Trials
Ultimately, clinical trials must be carried out in humans to discover how safe and effective a given monoclonal antibody is. Trials often accrue in sequential phases:
- Phase I: Evaluate safety and dosage.
- Phase II: Assesses efficacy and side effects in a larger group.
- Phase III: Confirms effectiveness and monitors long-term safety in diverse populations.
Successful trials provide the evidence needed for regulatory approval and widespread use.
Benefits of Monoclonal Antibody Therapies
Targeted Treatment
Because monoclonal antibodies can bind to simple antigens displayed by the malaria parasites, this form of treatment should have fewer side effects and offer more precise targeting.
Reduced Resistance Risk
Because untargeted antimalarial drugs overwhelm the parasite’s biochemistry, it’s easier for the parasite to develop resistance to broad-spectrum drugs than to monoclonal antibodies that attack a specific vulnerable component of their physiology. This is even more important now that the parasites mosquitos feed upon have become increasingly resistant to existing antimalarial drugs.
Complementary to Existing Therapies
Given judiciously, monoclonal antibodies can complement other antimalarial drugs like ACTs and contribute to the much-needed broad-spectrum response to malaria control and management.
Challenges and Considerations
Cost and Accessibility
Since mAb production and purification are still rather costly processes, and not widely disseminated in low-resource settings, efforts to reduce production costs and make access truly global are essential for the broader impact of mAb therapies.
Immunogenicity and Safety
Monoclonal antibodies are therapeutic agents like any other medicine, so researchers must evaluate them for immunological safety and potential allergic reactions or adverse effects that may arise during clinical testing.
Logistical and Distribution Issues
Getting monoclonal antibody therapies to the right patients at the right time requires robust healthcare infrastructure – and making sure these treatments are available when and where people most need them is crucial.
The Future of Monoclonal Antibody Therapies
Ongoing Research and Development
Research into monoclonal antibodies for malaria is active and continues to identify new targets and new medications. Future developments in biotechnology and immunology will no doubt cause a wave of new and even more effective and flexible medicines.
Combination Therapies
The investigators could achieve this by administering monoclonal antibodies not solely, but along with other antimalarials and vaccines, which would improve the effects of the standard drug or vaccine, which could ultimately lead to complete malaria control. This area of investigation focuses on identifying synergistic effects and the combination that works best.
Global Health Impact
If scaled up, the monoclonal antibody therapies might become a critical component of future malaria control. Recognizing the parasite, they can exert targeted therapeutic activities, and their potential to spread resistance is low.
Monoclonal antibody treatment is one of the most exciting recent developments in malaria therapy. Over the past couple of decades, monoclonal antibodies have evolved to the stage where they could play a crucial role in improving malaria treatment and prevention. It is hoped that this will decrease global malaria burden and help reach the goal of malaria eradication.
