Biology subjects

Bloch, E.

Publications and source records attributed to Bloch, E..

3 recordsLinked to original sources

bioRxiv2026

Protective near-germline antibodies to malaria elicited by RTS,S/AS01E vaccination in African infants

Malaria is a leading cause of childhood mortality, yet infant immune responses to vaccination remain poorly understood. Here, we characterize 88 monoclonal antibodies (mAbs) directed against the Plasmodium falciparum circumsporozoite protein cloned from African infants immunized with the RTS,S/AS01E malaria vaccine, identifying potent antiparasitic mAbs exhibiting molecular features resembling those observed in adults and minimal somatic hypermutation. Importantly, germline-reverted variants of four mAbs inducing sterile protection in vivo maintained high binding affinity and Fab-dependent parasite killing. Structural analyses revealed that a few amino acid replacements drive homotypic helical assemblies, fine-tuning parasite inhibition and protective efficacy. Thus, despite maturational constraints of early life, infants can generate potent antimalarial antibodies in a near-germline configuration, informing next-generation vaccine development for this vulnerable group.

immunology↗

bioRxiv2019

pH-Dependent Grafting of Cancer Cells with Antigenic Epitopes Promotes Selective Antibody-Mediated Cytotoxicity

A growing class of immunotherapeutic agents work by redirecting components of the immune system to recognize specific markers on the surface of cancer cells and initiate a selective immune response. However, such immunotherapeutic modalities will remain confined to a relatively small subgroup of patients until two major hurdles are overcome: (1) the specific targeting of cancer cells relative to healthy cells, and (2) the lack of common targetable tumor biomarkers among all patients. Here, we designed a unique class of agents that exploit the inherent acidic microenvironment of solid tumors to selectively graft the surface of cancer cells with immuno-engager epitopes for directed destruction by components of the immune system. Specifically, conjugates were assembled using an antigen that recruit antibodies present in human serum, and the pH(Low) Insertion Peptide (pHLIP), a unique peptide that selectively target tumors in vivo by anchoring onto cancer cell surfaces in a pH-dependent manner. We established that conjugates can recruit antibodies from human serum to the surface of cancer cells, and induce complement-dependent and antibody-dependent cellular cytotoxicity by peripheral blood mononuclear cells and also an engineered NK cell line. These results suggest that these agents have the potential to be applicable to treating a wide range of solid tumors and to circumvent the problem of narrow windows of selectivity.

immunology↗

bioRxiv2019

Disrupting the Transmembrane Domain Oligomerization of Protein Tyrosine Phosphatase Receptor J Promotes its Activity in Cancer Cells

Despite the critical regulatory roles that receptor protein tyrosine phosphatases (RPTP) play in mammalian signal transduction, the detailed structural basis for the regulation of their catalytic activity is not fully understood, nor are they generally therapeutically targetable. It is due, in part, to the lack of known natural ligands or selective agonists. In contrast to conventional structure-function relationship for receptor tyrosine kinases (RTKs), the activity of RPTPs has been reported to be suppressed by dimerization, which may prevent their access to their RTK substrates. We report here that: (i) homodimerization of PTPRJ (also known as DEP-1) is regulated by specific transmembrane (TM) residues, and (ii) disrupting these interactions can destabilize full-length PTPRJ homodimerization in cells, reduce the phosphorylation of EGFR (a known substrate) and downstream signaling effectors, antagonize EGFR-driven cell phenotypes, and promote substrate access. We demonstrate these points in human cancer cells using both mutational studies and through the identification of a peptide designed to bind to the PTPRJ TM domain. This peptide is the first example of such allosteric agonist of RPTPs. This study, therefore, provides not only fundamental structure-function insights on how PTPRJ activity is tuned by TM interactions in cells but also opportunities to develop a unique class of agents that could be used as tools to probe RPTPs signaling regulating mechanisms or for therapeutic purposes in cancers driven by RTK signaling.

biochemistry↗