Adrian Hugenmatter

All Publications

• Development of ACE2-tropic-betacoronavirus therapeutics for future pandemic preparedness. Nature communications Utz, A., Armbrust, M., Nguyen, T. T., Morris, M. K., Matthews, C. O., Kompella, P., Cao, Z., Ha, J. W., Violette, A., Brewer, R. C., Lanz, T. V., Robinson, W. H., Xu, D., Hanson, C., Hugenmatter, A., Kim, P. S. 2025

  Abstract

  A major challenge during viral pandemics is the ability to develop therapeutics whose efficacy can withstand viral genetic evolution. During the COVID-19 pandemic, five SARS-CoV-2 monoclonal antibody (mAb) therapeutics were rendered ineffective within a period of 2 years, leading to the U.S. FDA revoking their emergency use authorization. Here, we describe ReconnAb-multimers, a new therapeutic design that broadly and potently neutralize all tested betacoronaviruses that use host ACE2 as their receptor to enter cells. These ReconnAb-multimers have potent neutralization efficacy via avidity, enhanced breadth via a new pan-betacoronavirus-binding antibody that targets a highly conserved epitope on SARS-CoV-2 spike protein, and the potential for clinical development by using a catalytically inactive ACE2 component. We demonstrate that ReconnAb-multimers neutralize all SARS-CoV-2 pseudoviruses and authentic viral variants of concern (VOC) tested, with similar or higher potency than mAbs previously approved by the FDA; neutralize related pandemic-potential betacoronaviruses, including SARS-CoV, WIV1-CoV, PRD-0038, and merbecovirus HKU5-CoV-2; and despite a short half-life, protect female mice against authentic viral challenge with Omicron variant XBB.1.5. Our results highlight ReconnAb-multimers as a broad and highly potent therapeutic that could potentially withstand viral escape against current and future betacoronaviruses that require host ACE2 as a receptor.

  View details for DOI 10.1038/s41467-025-66805-6

  View details for PubMedID 41318533

• A human blood-brain barrier transcytosis assay reveals antibody transcytosis influenced by pH-dependent receptor binding. PloS one Sade, H., Baumgartner, C., Hugenmatter, A., Moessner, E., Freskgård, P. O., Niewoehner, J. 2014; 9 (4): e96340

  Abstract

  We have adapted an in vitro model of the human blood-brain barrier, the immortalized human cerebral microvascular endothelial cells (hCMEC/D3), to quantitatively measure protein transcytosis. After validating the receptor-mediated transport using transferrin, the system was used to measure transcytosis rates of antibodies directed against potential brain shuttle receptors. While an antibody to the insulin-like growth factor 1 receptor (IGF1R) was exclusively recycled to the apical compartment, the fate of antibodies to the transferrin receptor (TfR) was determined by their relative affinities at extracellular and endosomal pH. An antibody with reduced affinity at pH5.5 showed significant transcytosis, while pH-independent antibodies of comparable affinities at pH 7.4 remained associated with intracellular vesicular compartments and were finally targeted for degradation.

  View details for DOI 10.1371/journal.pone.0096340

  View details for PubMedID 24788759

  View details for PubMedCentralID PMC4005765

• The evolutionary origins of detoxifying enzymes: the mammalian serum paraoxonases (PONs) relate to bacterial homoserine lactonases. The Journal of biological chemistry Bar-Rogovsky, H., Hugenmatter, A., Tawfik, D. S. 2013; 288 (33): 23914-27

  Abstract

  Serum paraoxonases (PONs) are detoxifying lactonases that were first identified in mammals. Three mammalian families are known, PON1, 2, and 3 that reside primarily in the liver. They catalyze essentially the same reaction, lactone hydrolysis, but differ in their substrate specificity. Although some members are highly specific, others have a broad specificity profile. The evolutionary origins and substrate specificities of PONs therefore remain poorly understood. Here, we report a newly identified family of bacterial PONs, and the reconstruction of the ancestor of the three families of mammalian PONs. Both the mammalian ancestor and the characterized bacterial PONX_OCCAL were found to efficiently hydrolyze N-acyl homoserine lactones that mediate quorum sensing in many bacteria, including pathogenic ones. The mammalian PONs may therefore relate to a newly identified family of bacterial, PON-like "quorum-quenching" lactonases. The appearance of PONs in metazoa is likely to relate to innate immunity rather than detoxification. Unlike the bacterial PON, the mammalian ancestor also hydrolyzes, with low efficiency, lactones other than homoserine lactones, thus preceding the detoxifying functions that diverged later in two of the three mammalian families. The bifunctionality of the mammalian ancestor and the trade-off between the quorum-quenching and detoxifying lactonase activities explain the broad and overlapping specificities of some mammalian PONs versus the singular specificity of others.

  View details for DOI 10.1074/jbc.M112.427922

  View details for PubMedID 23788644

  View details for PubMedCentralID PMC3745338

• Directed evolution of serum paraoxonase PON3 by family shuffling and ancestor/consensus mutagenesis, and its biochemical characterization. Biochemistry Khersonsky, O., Rosenblat, M., Toker, L., Yacobson, S., Hugenmatter, A., Silman, I., Sussman, J. L., Aviram, M., Tawfik, D. S. 2009; 48 (28): 6644-54

  Abstract

  Serum paraoxonases (PONs) are calcium-dependent lactonases with anti-atherogenic and detoxification functions. Here we describe the directed evolution and characterization of recombinant variants of serum paraoxonase PON3 that express in an active and soluble manner in Escherichia coli. These variants were obtained by combining family shuffling and phylogeny-based mutagenesis: the limited diversity of accessible, cloned PON3 genes was complemented by spiking the shuffling reaction with ancestor/consensus mutations, mutations to residues that comprise the consensus or appear in the predicted ancestors of the PON family. We screened the resulting libraries for PON3's lactonase activity while ensuring that the selected variants retained the substrate specificity of wild-type mammalian PON3s. The availability of highly stable, recombinant PON3 that is free of all other serum components enabled us to explore unknown biochemical features of PON3, including its binding to HDL particles, the effect of HDL on PON3's stability and enzymatic activity, and ex vivo tests of its anti-atherogenic properties. Overall, it appears that PON3 possesses properties very similar to those of PON1: the enzyme's lactonase activity is selectively stimulated by binding to apoAI-HDL, with a concomitant increase in its stability. PON3 also exhibits potentially anti-atherogenic functions, although at levels lower than those of PON1.

  View details for DOI 10.1021/bi900583y

  View details for PubMedID 19492856