Presentation Information
[3FMBS-11]Antibody optimization by site-directed chemical modification
○Jose Caaveiro1 (1. Kyushu University, Faculty of Pharmaceutical Sciences (Japan))
Keywords:
Broadly neutralizing antibody,Chemical modification,Structural biology,HIV-1,lipid-protein interaction
As demonstrated during the COVID-19 pandemic, infectious diseases remain a critical public health challenge. Rather than just a distant, looming danger, they present a tangible threat to our daily lives and global well-being. In this presentation, we will explore a straightforward hybrid strategy for generating novel antibody modalities through a combination of mutation and chemical modification. Our focus today is on antibodies targeting HIV-1, the virus responsible for AIDS, which continues to be a leading cause of morbidity and mortality worldwide.
Specifically, we will examine the broadly neutralizing anti-HIV-1 antibodies (bnAbs) known as 4E10 and 10E8. These bnAbs bind to the membrane-proximal external region (MPER), a segment of the gp41 protein situated at the water-membrane interface. Because the MPER is highly conserved, antibodies directed against it exhibit the broadest neutralization range reported to date for any anti-HIV-1 bnAbs. Furthermore, since this region is critical for the membrane fusion process that enables viral genetic material to enter host cells, the MPER represents a highly promising therapeutic target.
However, despite their exceptional breadth, these antibodies currently suffer from low overall efficacy, which restricts their viability as clinical therapeutics. To address this, we will detail a strategy to significantly boost their potency by introducing precise structural changes via site-directed mutagenesis coupled with chemical modification. We will outline the structural and thermodynamic mechanisms underlying this enhanced potency. Finally, the presentation will conclude with a discussion on the remarkable activity of these modified antibodies, the inherent challenges of this hybrid approach, and potential methods to mitigate those limitations.
Specifically, we will examine the broadly neutralizing anti-HIV-1 antibodies (bnAbs) known as 4E10 and 10E8. These bnAbs bind to the membrane-proximal external region (MPER), a segment of the gp41 protein situated at the water-membrane interface. Because the MPER is highly conserved, antibodies directed against it exhibit the broadest neutralization range reported to date for any anti-HIV-1 bnAbs. Furthermore, since this region is critical for the membrane fusion process that enables viral genetic material to enter host cells, the MPER represents a highly promising therapeutic target.
However, despite their exceptional breadth, these antibodies currently suffer from low overall efficacy, which restricts their viability as clinical therapeutics. To address this, we will detail a strategy to significantly boost their potency by introducing precise structural changes via site-directed mutagenesis coupled with chemical modification. We will outline the structural and thermodynamic mechanisms underlying this enhanced potency. Finally, the presentation will conclude with a discussion on the remarkable activity of these modified antibodies, the inherent challenges of this hybrid approach, and potential methods to mitigate those limitations.
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