Monoclonal antibodies, such as the breast cancer therapeutic Herceptin, have revolutionised the treatment of cancer and inflammatory conditions. Will over $30 billion sales in 2011, they have also spawned a growing biotech industry. We have a generated a highly specific monoclonal antibody, which has shown efficacy in models of disease. This project will further advance and develop this monoclonal, allowing us to initiate clinical studies in patients.
Development Of Stable Human Antibody Phage Display Libraries
Funder
National Health and Medical Research Council
Funding Amount
$539,644.00
Summary
Antibodies are blockbuster therapeutics for the treatment of cancer and inflammation. Unfortunately, they often display limited stability which greatly hinders development and production. This project focuses on the construction of large libraries of stable antibodies, thereby streamlining the development of new therapeutics.
Use Of Peptides From Phage Display Libraries To Probe The Function Of AMA-1 And Other Malaria Surface Proteins
Funder
National Health and Medical Research Council
Funding Amount
$316,650.00
Summary
Malaria remains a major cause of mortality and morbidity worldwide. Much current research is aimed at exploring the molecular interactions between malarial proteins and host components in order to gain a deeper understanding of parasite virulence mechanisms, design alternative anti-malarial approaches and improve vaccine design. The apical membrane antigen-1( AMA-1) is a surface exposed protein which is thought to play a crucial role in invasion of red blood cells by malaria parasites, and is cu ....Malaria remains a major cause of mortality and morbidity worldwide. Much current research is aimed at exploring the molecular interactions between malarial proteins and host components in order to gain a deeper understanding of parasite virulence mechanisms, design alternative anti-malarial approaches and improve vaccine design. The apical membrane antigen-1( AMA-1) is a surface exposed protein which is thought to play a crucial role in invasion of red blood cells by malaria parasites, and is currently one of the leading asexual stage vaccine candidates. While antibodies to AMA-1 prevents malaria invasion, little is known about the role of the antigen in the invasion process. The aim of this proposal is to investigate the molecular interactions that makes AMA-1 an important player in the invasion process. We propose to map the regions of AMA-1 responsible for binding a set of peptides which we have isolated from random peptide libraries. Since these peptides inhibit the invasion of parasites into red blood cells, regions of AMA1- that bind these peptides will be of functional significance. A further outcome will be the identification of peptide residues essential for the inhibition of invasion followed by in vitro evolution of these peptides to improve their binding and inhibitory properties. A molecular description of how AMA1 binding peptides prevent parasite invasion of host erythrocytes will improve our understanding of the invasion process, and aid in improving vaccines based on AMA-1. Furthermore, this peptide-AMA-1 interaction will be assessed as a possible target for the development of novel anti-malarial therapies. Using random peptide libraries we have selected peptides that specifically bind to other merozoite surface proteins thought to be involved in merozoite invasion of erythrocytes. The ability of these peptides to inhibit merozoite invasion will be examined and characterised as described above.Read moreRead less
Structural Basis For Inhibition Of Malaria Invasion By Targeting The Apical Membrane Antigen Of Plasmodium Falciparum.
Funder
National Health and Medical Research Council
Funding Amount
$434,134.00
Summary
3 million children die every year from malaria infections. A leading vaccine candidate is a protein from the malaria parasite called AMA1. Humans that have been infected with malaria make antibodies to this protein which can kill parasites, however little is known about how this occurs. We aim to identify regions of the protein that generate antibodies that prevent malaria parasites from invading human cells and help in the search for a vaccine against malaria.
Structure And Interactions Of The Malarial Vaccine Candidate AMA1
Funder
National Health and Medical Research Council
Funding Amount
$351,000.00
Summary
Malaria remains one the most lethal infectious diseases in the world today. It is directly responsible for 1-2 million deaths annually, many of these in children under 5 years of age. More than 300 million clinical cases are reported annually and over 40% of the global population (in excess of 2 billion people) are at risk. There is an urgent need for a vaccine against this disease, particularly because of the recent increase in forms of the parasite resistant to many of the best anti-malarial d ....Malaria remains one the most lethal infectious diseases in the world today. It is directly responsible for 1-2 million deaths annually, many of these in children under 5 years of age. More than 300 million clinical cases are reported annually and over 40% of the global population (in excess of 2 billion people) are at risk. There is an urgent need for a vaccine against this disease, particularly because of the recent increase in forms of the parasite resistant to many of the best anti-malarial drugs. AMA1 is an asexual stage antigen and a leading vaccine candidate. Little is known about the function of this protein, but it has been proposed to play a role in invasion of red blood cells. A clearer understanding of the structure of parasite antigens such as AMA1 that induce a protective response in infected individuals would provide a stimulus to research into recombinant antigens as vaccines and a deeper understanding of host-parasite interactions. The aims of this project are to determine the three-dimensional structures of the three major structural domains of AMA1 and of the complete AMA1 antigen. We shall also determine the structures, both in aqueous solution and bound to AMA1, of small peptides identified by phage display as being capable of binding to AMA1 and blocking parasite entry into red blood cells. The overall goal of this work is to determine the structure of AMA1 and define the structural basis for its interaction with small peptides capable of blocking its activity as well as the structural features necessary for AMA1 to react with protective antibodies. The structure of AMA1 will provide a molecular basis for the design of engineered antigens capable of eliciting a protective immune response against AMA1. The inhibitory peptide structures will likewise provide a molecular basis for the design of non-peptidic blockers of AMA1. Either or both of these may be useful therapeutics leads in the fight against malaria.Read moreRead less