Introduction and Background of the Project

1. Introduction

In October 2021, the World Health Organization (WHO) recommended broad use of RTS,S, the world’s first malaria vaccine, in children at risk. Although a significant reduction in malaria disease and deaths is anticipated after implementation of this recommendation, new intervention tools are still needed in fighting against malaria. RTS,S functions primarily by inducing high titer antibodies to the invariant repeat region of the P. falciparum CS protein. Highly potent monoclonal antibodies (mAbs) in protective antisera are likely to be promising tools for malaria intervention. The project team aims to isolate and develop a potent anti-CSP mAb for malaria prevention. The project is enabled by access to a panel of potent anti-CSP mAbs, identified from volunteers who were protected against P. falciparum challenge following immunization with RTS,S. Applying in silico, in vitro, and in vivo methodologies the project team characterized hundreds candidate mAbs and optimize the selected 4 mAbs for enhanced potency and serum stability. After further evaluation for to address potential safety concerns, one final mAb will be advanced to further preclinical and clinical development as a tool for malaria intervention.

2. Project objective

The objective of this project is to complete preclinical development works to support future IND submission for a proof-of-concept clinical trial including controlled human malaria infection (CHMI). The long-term goal of this project is to secure a WHO policy recommendation and financing for a monoclonal antibody that prevents P. falciparum malaria in young children, and potentially pregnant women, living in areas of seasonal transmission in sub-Saharan Africa. 1) Manufacture a cell bank for the lead mAb production, and demonstrate the efficacy of the lead mAb in a mouse challenge model 2) Complete process development and manufacture the lead mAb suitable for a GLP toxicology study 3) Complete a pre-IND meeting with US FDA 4) Complete preliminary Cost-of-Goods (COGs) analysis for anti-malaria infection mAbs, and develop an initial integrated product development and policy plan (iPDPP).

3. Project design

The project is built on successful completion of prior works including 1) in vitro and in vivo screening for a lead panel of mAbs; 2) engineering the lead panel mAbs to enhance potency and serum stability, and to minimize development risk identified by in silico analyses; 3) minimizing risk of selected mAbs with cross-reactivity to human tissues by early screening for binding to human tissues and human membrane proteins; 4) confirming in vivo protective efficacy and pharmacokinetics of the selected mAbs in mouse models; 5), initiate cell line development and select one to advance; and 6) established capabilities of mAb production process development, optimization, and production. The proposed work will start with production and release of a pre-master cell bank for production of the mAb of final selection. The manufacture process for the mAb will be developed and optimized to confirm conditions for production of the mAb lot suitable for GLP toxicity studies, and to enable future scale up production for clinical trial materials. In addition, formulation development will be conducted to enable stability of the mAb at high concentration to accommodate potential subcutaneous injection. The mAb materials produced during the process development and the mAb lot for the GLP toxicity studies will be evaluated in mouse challenge model to confirm protective efficacy. A pre-IND meeting will be conducted with US FDA. We will also conduct IND-enabling GLP-toxicology studies to evaluate repeated dose toxicity and tissue-cross reactivity of the mAb. In parallel, a COGs analysis will be conducted with information on methods of production, product configuration (vial type and size), and a competitive landscape analysis will be conducted with information on mAbs in development for malaria prevention. Finally, an iPDPP will be drafted for alignment clinical, regulatory, manufacturing, and policy strategies for global health deployment of mAbs and alike.

How can your partnership (project) address global health challenges?

In 2020, there were an estimated 241 million cases of malaria worldwide, and 627,000 deaths from malaria, highlighting the urgent need for new malaria interventions. Seasonal malaria chemoprevention (SMC) in children living in the Sahel region of Africa is associated with high efficacy (~80%); however, implementation challenges associated with the need for monthly dosing, drug resistance in eastern and southern Africa, and lack of suitability for pregnant women has limited impact.  A first-generation malaria vaccine, RTS,S, delivered through highly effective routine immunization programs in endemic countries, holds promise for significant public health impact when targeted to children living in moderate to high transmission settings in sub-Saharan Africa.  However, it requires 4 doses which is relatively expensive, and is associated with modest efficacy that wanes relatively quickly.  Monoclonal antibodies offer the potential to overcome the limitations associated with both SMC and first-generation vaccines, by providing high level, seasonal protection against all P. falciparum strains, following a single administration. This technology has the potential to reduce the implementation burden associated with SMC on already challenged health systems.

What sort of innovation are you bringing in your project?

First, a unique innovative advantage of this project is the access of CS-specific antibodies from volunteers who were protected following immunization with the RTS,S vaccine. Consistent with the immunodominance of the protective CS-specific epitopes in the RTS,S vaccine, our panel of well-characterized plasmablasts contains a high proportion of sequences specific for our target epitope (i.e. CS-repeats).  This focused approach differs from other projects where CS antibodies were from volunteers either immunized with irradiated sporozoites or naturally infected.

Second, we start with “end” in mind and bring in a “line of sight” approach to conduct CoGs analysis and development of iPDPP for mAbs as tools for malaria intervention.  This is to ensure rigorous assessment of the critical value drivers to attain cost effectiveness and high community acceptance, as well as inform our TPP. 

Last but not the least, our project combines experience of a world class consortium focused on global health impact. The consortium is comprised of a global non-profit organization (PATH) with unrivaled experience in malaria and product development; two biopharma companies (Eisai and GSK) with deep commitments to global health, extensive malaria and monoclonal research, and development and commercialization experience; and a premier malaria academic research partner (Ehime University). 

Role and Responsibility of Each Partner

PATH is responsible for overall conduct of the study.  As PATH will be the IND holder, it will be the primary contact with the US FDA (or other regulatory agency if a non-US study). PATH will manage all contracts related to IND-enabling GLP toxicology studies.  PATH is also responsible for COGs analysis and iPDPP development.

GSK is responsible for the identification of lead molecules with the appropriate properties in terms of efficacy, half-life and developability, that could progress to cell line development to produce a pre-master cell bank.  GSK will also be responsible to perform in vivo studies in mouse challenge model to assess protective efficacy.

Eisai is responsible for the optimization and process development for production of the mAb suitable for the IND-enabling GLP toxicity studies.  Eisai is also responsible for formulation development study to ensure stability of a formulation with highest possible concentration.

Ehime University is responsible for development and implementation of an assay to evaluate ligand binding potency of the mAb, as part of release assay for the mAb. 

Final Report

1. Project objective:

To complete preclinical development to support an Investigational New Drug (IND) submission for a Phase 1 trial including a controlled human malaria infection study. Activities:

1. 1. Manufactured cell bank for lead monoclonal antibody (mAb) production and demonstrated efficacy in mouse challenge models.
2. 2. Completed process development and manufactured suitable batch of material for Good Laboratory Practice (GLP) toxicology studies.
3. 3. Completed pre-IND meeting with US Food and Drug Administration (FDA).
4. 4. Completed preliminary cost-of-goods (COGs) analysis and developed integrated Product Development and Policy Plan (iPDPP) to support priority use case of prevention of Plasmodium falciparum malaria in young African children.

2. Project design:

This project was built on the successful selection and engineering of a lead mAb identified in an RTS,S/AS01 malaria vaccine clinical study. The project team began with production of a pre-master cell bank (pre-MCB) and the development of manufacturing and formulation processes to enable the production of a batch used in IND-enabling GLP toxicology studies. These studies evaluated repeated-dose toxicity and toxicokinetics, and reactivity against human tissues. The team then conducted COGs and competitive landscape analyses and drafted an initial iPDPP to guide clinical, regulatory, manufacturing, and policy efforts, in alignment with the intended use case.

3. Results, lessons learned:

The project team successfully achieved all proposed objectives and milestones in alignment with the allocated budget. Key results include:

• ・The team produced a pre-MCB and confirmed the efficacy of a batch of the lead mAb manufactured using the pre-MCB in two mouse models of malaria infection. One model used a wild-type P. falciparum parasite in mice engrafted with human hepatocytes, and the other used wild-type mice challenged with a P. berghei transgenic parasite expressing P. falciparum circumsporozoite protein.
• ・The team developed manufacturing and formulation processes to optimize the yield and solubility/stability of the mAb. A batch was produced, released, and placed on stability to be used for GLP toxicology studies to support future regulatory submissions. We also developed a binding assay that was used in the potency assessment as part of the stability program for the mAb.
• ・The team conducted a Type-C meeting with the US FDA to discuss the adequacy of the non-clinical studies to support a Phase 1 trial and the overall clinical study plan. The FDA’s written response was clear and in general agreement with our proposed plans.
• ・ The team completed two nonclinical GLP toxicology studies. The GLP repeated-dose toxicology and toxicokinetics study in rats evaluated the mAb, and the doses tested were well tolerated. The No Observed-Adverse-Effect-Level (NOAEL) was concluded at the highest doses tested. The mAb also showed no cross-reactivity with 39 human tissues tested in a GLP tissue cross-reactivity study. These results support progression of the mAb into a first-in-human Phase 1 trial.
• ・ The team conducted preliminary COGs and competitive landscape analyses and drafted an iPDPP to enable a line-of-sight through the development, approval, and policy recommendation for the mAb in alignment with the primary use case: prevention of P. falciparum malaria in young African children. While these analyses will be repeated and the iPDPP revised during the evolution of the technology as new information becomes available, the outcomes of these exercises enhanced our project planning for the development of this mAb for malaria prophylaxis.