Structural basis for antibody recognition of the NANP repeats in
            <i>Plasmodium falciparum</i>
            circumsporozoite protein

Oyen, David; Torres, Jonathan L.; Wille-Reece, Ulrike; Ockenhouse, Christian F.; Emerling, Daniel; Glanville, Jacob; Volkmuth, Wayne; Flores-García, Yevel; Zavala, Fidel; Ward, Andrew B.; King, C. Richter; Wilson, Ian A.

doi:10.1073/pnas.1715812114

Cited by 123 publications

(248 citation statements)

References 55 publications

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“…Such a conformation is very similar to turns observed for unbound NANP peptides in solution and in crystal structures of free and antibody-bound peptides (Fig. 4d) [25][26][27][28][29] . An isolated DPN motif is also present in the 282-383 C-terminal peptide, which may explain its binding to MGG4 ( Fig.…”

Section: Structural Analysis Of the Mgg4 Antibody Reveals The Basis Fsupporting

confidence: 79%

A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein

Tan

Sack

Oyen

et al. 2018

Nat Med

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187

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Immunization with attenuated Plasmodium falciparum sporozoites (PfSPZ) has been shown to be protective, but the features of the antibody response induced by this treatment remain unclear. To investigate this response at high resolution, we isolated IgM and IgG monoclonal antibodies from Tanzanian volunteers who were immunized by repeated injection of irradiated PfSPZ and who were found to be protected from controlled human malaria infection (CHMI) with infectious homologous PfSPZ. All IgG monoclonals isolated bound to P. falciparum circumsporozoite protein (PfCSP) and recognized distinct epitopes in the N-terminus, NANP repeat region, and C-terminus. Strikingly, the most effective antibodies, as assessed in a humanized mouse model, bound not only to the repeat region, but also to a minimal peptide at the PfCSP N-terminal junction that is not in the RTS,S vaccine. These dual-specific antibodies were isolated from different donors and used VH3-30 or VH3-33 alleles carrying tryptophan or arginine at position 52. Using structural and mutational data, we describe the elements required for germline recognition and affinity maturation. Our study provides potent neutralizing antibodies and relevant information for lineage-targeted vaccine design and immunization strategies.

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Section: Structural Analysis Of the Mgg4 Antibody Reveals The Basis Fsupporting

confidence: 79%

A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein

Tan

Sack

Oyen

et al. 2018

Nat Med

Self Cite

187

265

View full text Add to dashboard Cite

show abstract

“…It has an N-terminal domain containing region I, followed by a tandem repeat region consisting of the asparagine-alanine-asparagine-proline (NANP) amino acid (aa) motif repeated 20 to 40 times, interspaced four times with asparagine-valine-aspartate-proline (NVDP) and asparagine-proline-aspartateproline (NPDP). It has a C-terminal domain (CTD), comprising region II and a glycosylphosphatidylinositol (GPI) anchor sequence [38,39] (Fig. 2a, c).…”

Section: Genetically-attenuated Sporozoite Vaccinesmentioning

confidence: 99%

“…An immunological response against NANP repeats has been a crucial point in developing CSP-basad vaccines. An analysis of the interaction between human monoclonal antibodies (mAbs) (RTS,S vaccine-derived 31, 317, Mal1C, Mal2A and Mal3B) and NANP repeats has led to identifying minimal epitope binding and confirming that an increase in the amount of Ab contacts can improve affinity for the repeats in this sequence [38,40].…”

Section: Genetically-attenuated Sporozoite Vaccinesmentioning

confidence: 99%

Plasmodium falciparum pre-erythrocytic stage vaccine development

Molina-Franky

Cuy-Chaparro

Camargo

et al. 2020

Malar J

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Worldwide strategies between 2010 and 2017 aimed at controlling malarial parasites (mainly Plasmodium falciparum) led to a reduction of just 18% regarding disease incidence rates. Many biologically-derived anti-malarial vaccine candidates have been developed to date; this has involved using many experimental animals, an immense amount of work and the investment of millions of dollars. This review provides an overview of the current state and the main results of clinical trials for sporozoite-targeting vaccines (i.e. the parasite stage infecting the liver) carried out by research groups in areas having variable malaria transmission rates. However, none has led to promising results regarding the effective control of the disease, thereby making it necessary to complement such efforts at finding/introducing new vaccine candidates by adopting a multi-epitope, multi-stage approach, based on minimal subunits of the main sporozoite proteins involved in the invasion of the liver.

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“…Currently there are 3 mAbs published with potent activity against the circumsporozoite protein, CSP, and these can reduce the parasitaemia in sporozoite-infected FRG (triple mutant Fah/Raγ2/IL2Rγ) mice that carry a human liver implant [132]. These mAbs include mAb317, cloned from B cells obtained from a patient in the recent RTS,S vaccine trial [133], CIS43 (circumsporozoite protein 43 [56]), and a set that included MGU12 [134], cloned from patients vaccinated with irradiated sporozoites. Antibodies that block the invasion process of the red blood cells by merozoites represent another possible approach.…”

Section: Malariamentioning

confidence: 99%

Reassessing therapeutic antibodies for neglected and tropical diseases

et al. 2020

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In the past two decades there has been a significant expansion in the number of new therapeutic monoclonal antibodies (mAbs) that are approved by regulators. The discovery of these new medicines has been driven primarily by new approaches in inflammatory diseases and oncology, especially in immuno-oncology. Other recent successes have included new antibodies for use in viral diseases, including HIV. The perception of very high costs associated with mAbs has led to the assumption that they play no role in prophylaxis for diseases of poverty. However, improvements in antibody-expression yields and manufacturing processes indicate this is a cost-effective option for providing protection from many types of infection that should be revisited. Recent technology developments also indicate that several months of protection could be achieved with a single dose. Moreover, new methods in B cell sorting now enable the systematic identification of high-quality antibodies from humanized mice, or patients. This Review discusses the potential for passive immunization against schistosomiasis, fungal infections, dengue, and other neglected diseases.PLOS Neglected Tropical Diseases | https://doi.interactions have proved difficult to block. In addition, there has been great progress in the development of technology. Early generations of antibodies for human use were developed from mAbs developed in mice, antibodies that were then humanized. Recently, the technology used peptide and antibody display on phages, for which part of the 2018 Nobel Prize in Chemistry was awarded to Sir Gregory P. Winter [6]. More recently, new technologies have been developed to clone antibodies from memory B cells [7] or plasma B cells [8, 9], allowing the isolation of individual antibodies from patients with viral infections-approaches that can be applied to any infectious disease.A second reason for the popularity of antibodies in recent years is their success rate in clinical development. Once an antibody reaches testing in humans, it has a success rate of 17% to 25% for approval as a new medicine [10], compared with 5% to 10% for small molecules. This success rate is partly due to the exquisite selectivity of mAbs, enabling them to distinguish between closely related molecular targets. In the case of infectious disease, this selectivity can be absolute, since antibodies can be generated that are specific for the invading pathogen and do not cross-react with host tissues. This lack of cross-reactivity with human tissue can be confirmed by immunohistochemistry on both adult and embryonic tissues prior to the start of clinical trials. This is in stark contrast to small molecules, in which sometimes unexpected onand off-target safety signals are frequently seen in the later stages of clinical development, resulting in expensive late-stage attrition. In addition, antibodies show a relatively narrow range of variation in pharmacokinetic exposure, facilitating early estimation of the human effective dose. This is unlike true xenobiotics, whose metabolism an...

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Structural basis for antibody recognition of the NANP repeats in Plasmodium falciparum circumsporozoite protein

Cited by 123 publications

References 55 publications

A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein

A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein

Plasmodium falciparum pre-erythrocytic stage vaccine development

Reassessing therapeutic antibodies for neglected and tropical diseases

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