Molecular determinants of cross-reactivity and potency by VH3-33 antibodies against the Plasmodium falciparum circumsporozoite protein

Thai, Elaine; Murugan, Rajagopal; Binter, Špela; Burn Aschner, Clare; Prieto, Katherine; Kassardjian, Audrey; Obraztsova, Anna S.; Kang, Ryu Won; Flores-Garcia, Yevel; Mathis-Torres, Shamika; Li, Kan; Horn, Gillian Q.; Huntwork, Richard H.C.; Bolscher, Judith M.; de Bruijni, Marloes H.C.; Sauerwein, Robert; Dennison, S. Moses; Tomaras, Georgia D.; Zavala, Fidel; Kellam, Paul; Wardemann, Hedda; Julien, Jean-Philippe

doi:10.1016/j.celrep.2023.113330

Cited by 7 publications

(3 citation statements)

References 71 publications

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“…This strong B cell activation, presumably mediated through the cross-linking of multiple BCRs at the B cell surface (53), has been suggested to limit affinity maturation in germinal centers, potentially due to early exit of B cells, favouring the elicitation of short-term low-affinity Abs to CSP over durable high-affinity responses, thus leading to suboptimal protective responses (54). However, this phenomenon may potentially be altered with the development of cross-reactive responses against repeats of slightly different content (55) (56) (57). Whether such insights extend to other anti-repeats Ab responses in general and anti-glutamate rich repeats in particular remains largely unexplored.…”

Section: Discussionmentioning

confidence: 99%

Target-agnostic identification of human antibodies toPlasmodium falciparumsexual forms reveals cross stage recognition of glutamate-rich repeats

Amen,

Yoo,

Fabra-García

et al. 2023

Preprint

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Circulating sexual stages ofPlasmodium falciparum (Pf)can be transmitted from humans to mosquitoes, thereby furthering the spread of malaria in the population. It is well established that antibodies (Abs) can efficiently block parasite transmission. In search for naturally acquired Ab targets on sexual stages, we established an efficient method for target-agnostic single B cell activation followed by high-throughput selection of human monoclonal antibodies (mAbs) reactive to natural sexual stages ofPfin the form of gamete and gametocyte extract. We isolated mAbs reactive against a range ofPfproteins including well-established targets Pfs48/45 and Pfs230. One of these mAbs, B1E11K, was cross-reactive to various proteins containing glutamate-rich repetitive elements expressed at different stages of the parasite life cycle. A crystal structure of two B1E11K Fab domains in complex with its main antigen, RESA, expressed on asexual blood stages, showed binding of B1E11K to a repeating epitope motif in a head-to-head conformation engaging in affinity-matured homotypic interactions. Thus, this mode of recognition ofPfproteins, previously described only for PfCSP, extends to other repeats expressed across various stages. The findings augment our understanding of immune-pathogen interactions to repeating elements of thePlasmodiumparasite proteome and underscore the potential of the novel mAb identification method used to provide new insights into the natural humoral immune response againstPf.SummaryProteins with amino acid repeats enriched in glutamate residues are prominently expressed in the asexual and sexual stages ofPlasmodium falciparum(Pf), the main causative agent of malaria. Here, we present a target-agnostic approach for the isolation of sexual stage antibodies (Abs), leading to the identification of B1E11K, an Ab cross-reactive to glutamate-rich repeats in proteins present in various life cycle stages ofPf. The Ab binds in a head-to-head conformation, leveraging affinity-matured homotypic interactions – an uncommon characteristic of Ab somatic hypermutation that results in the optimization of Ab-Ab interactions in the context of binding their repetitive epitope. Our data provides further credence that repetitive elements ofPfcan significantly modulate the humoral response, and that antibody recognition through homotypic interactions is occurring throughout thePflife cycle.

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Section: Discussionmentioning

confidence: 99%

Target-agnostic identification of human antibodies toPlasmodium falciparumsexual forms reveals cross stage recognition of glutamate-rich repeats

Amen,

Yoo,

Fabra-García

et al. 2023

Preprint

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“…Affinity measurement of stability improved mAb 4493 variants carrying LS mutations with peptides were measured using the Carterra LSA SPR platform and CMD200M sensor chips (Carterra) at 25°C as described before (Thai et al, 2023). In brief, the chip was directly immobilized with 10 μg/mL of variant mAbs through amine-coupling in 10 mM Sodium Acetate at pH 4.5 and unreactive esters were quenched using 1 M ethanolamine-HCl at pH 8.5.…”

Section: Surface Plasmon Resonancementioning

confidence: 99%

“…We previously reported that cross-reactivity to the PfCSP central repeat domain and Njunction is linked to antibody affinity, suggesting that the immunoglobulin (Ig) gene somatic hypermutation (SHM) process, in which B cells accumulate mutations during ongoing immune responses in germinal center (GC) reactions, might contribute to the generation of high-affinity cross-reactive antibodies (Murugan et al, 2020;Thai et al, 2023). Here, we addressed this question by experiments and molecular dynamics simulation for the recombinant monoclonal antibody (mAb) 4493, a somatically mutated, highly cross-reactive and protective human anti-PfCSP mAb (Murugan et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Somatic hypermutation-mediated paratope flexibility improves the cross-reactivity of human malaria antibodies

Murugan,

Hanke,

Oludada

et al. 2024

Preprint

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The protective capacity of antibodies targeting circumsporozoite protein on sporozoites of the malaria parasitePlasmodium falciparum(PfCSP) is linked to high affinity and cross-reactivity with the PfCSP central repeat domain and N-terminal junction. However, the role of somatic hypermutation (SHM) in the development of such antibodies remains unclear. Here we define the contributions of SHM to the high affinity and strong repeat and N-junction cross-reactivity of the potent anti-PfCSP monoclonal antibody (mAb) 4493 and of similar antibodies with shared SHM and affinity maturation trajectories. Molecular dynamics simulations reveal that SHM reduces the flexibility of the unbound mAb 4493 but increases the flexibility of the antigen-bound complex, thereby lowering the entropic cost for antigen binding. Furthermore, we identify an inverse relation between antibody affinity and serum stability, which limits the protective capacity of these antibodies. Our study provides molecular level evidence for the different roles that the SHM process plays in increasing VH3-49+Vκ3-20 antibody affinity and cross-reactivity and demonstrates how antibody affinity maturation can negatively impact antibody stability and thereby function.

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Monoclonal antibodies to the circumsporozoite proteins as an emerging tool for malaria prevention

Wang,

Idris,

Kisalu

et al. 2024

Nat Immunol

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Molecular determinants of cross-reactivity and potency by VH3-33 antibodies against the Plasmodium falciparum circumsporozoite protein

Cited by 7 publications

References 71 publications

Target-agnostic identification of human antibodies toPlasmodium falciparumsexual forms reveals cross stage recognition of glutamate-rich repeats

Target-agnostic identification of human antibodies toPlasmodium falciparumsexual forms reveals cross stage recognition of glutamate-rich repeats

Somatic hypermutation-mediated paratope flexibility improves the cross-reactivity of human malaria antibodies

Monoclonal antibodies to the circumsporozoite proteins as an emerging tool for malaria prevention

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