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bioRxiv · 10.1101/2022.04.12.488063

Performance of novel antibodies for lipoarabinomannan to develop diagnostic tests for Mycobacterium tuberculosis

Cantera, J. L.·Lillis, L. M.·Peck, R. B.·Moreau, E.·Schouten, J. A.·Davis, P.·Drain, P. K.·Andama, A.·Pinter, A.·Kawasaki, M.·Kallenius, G.·Sundling, C.·Dobos, K. M.·Flores, D.·Chatterjee, D.·Murphy, E.·Halas, O. R.·Boyle, D. S.
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Abstract

Lipoarabinomannan (LAM), a component of the Mycobacterium tuberculosis (MTB) cell wall, is detectable in the urine of MTB infected patients with active tuberculosis (TB). LAM-specific antibodies (Igs) have been developed by a variety of traditional and recombinant methods for potential use in a rapid diagnostic test (RDT). We evaluated the analytical performance of the TB LAM Igs to identify pairs that offer superior performance over existing urine LAM tests. We assessed 25 new and 4 existing Igs in a matrixed format using a multiplex electrochemiluminescence-based liquid immunoassay. A total of 841 paired Ig combinations were challenged with in vitro cultured LAM (cLAM) derived from MTB strains representing diverse phylogenetic lineages, alongside urinary LAM (uLAM) from the urine of adults with active pulmonary TB. Analytical sensitivity of down-selected Ig pairs was determined using MTB Aoyama-B cLAM, while diagnostic accuracy was determined using clinical samples. When testing cLAM, the reactivity of Ig pairs was similar across MTB lineages 1-4 but lineage 5:6 had significantly more reactivity among Ig pairs. Overall, 41 Ig pairs had a strong binding affinity to cLAM, as compared to the reference pair of S4-20/A194-01, and 28 Ig pairs therein exhibited a strong affinity for both cLAM and uLAM. Retrospective testing on clinical urine specimens demonstrated varying sensitivities (12-80%) and specificities (14-100%). The five top pairs had a similar analytical limit of detection to the reference pair but in four instances, the sensitivity and specificity with clinical uLAM samples was poor. Overall, epitopes presented by uLAM are different from cLAM, which may affect antibody performance when testing uLAM in patient samples. Several new Ig pairs had similar ranges of high sensitivity to cLAM but overall, there were no new candidate Ig pairs identified in this round of screening with increased performance with uLAM as compared to an existing optimal pair.

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Cantera, J. L., Lillis, L. M., Peck, R. B., Moreau, E., Schouten, J. A., Davis, P., Drain, P. K., Andama, A., Pinter, A., Kawasaki, M., Kallenius, G., Sundling, C., Dobos, K. M., Flores, D., Chatterjee, D., Murphy, E., Halas, O. R., Boyle, D. S.. 2022-04-12. Performance of novel antibodies for lipoarabinomannan to develop diagnostic tests for Mycobacterium tuberculosis. https://doi.org/10.1101/2022.04.12.488063

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