Week 3, August 2024: VHH Antibodies Everywhere

VHH antibodies, also known as nanobodies, are single-domain antibodies that are derived from camelid heavy-chain antibodies. Due to their small size (~ 15 kDa) and diverse applications in bio-derived therapeutics, these antibodies have widespread attention in the research and development community, with some examples below from just this week! 

This week, researchers from the U.S. Naval Research Laboratory published a paper on TEMPRO, a novel predictive modeling approach for estimating the melting temperature (Tm) of VHH antibodies using computational methods. TEMPRO integrates biophysical features such as Evolutionary Scale Modeling (ESM) embeddings, NetSurfP3 structural predictions, pLDDT scores from AlphaFold2, and sequence physicochemical characteristics to predict Tm. Further validation confirmed its reliability, making TEMPRO a valuable tool for optimizing VHH antibodies and highlighting the potential of protein embeddings in enhancing downstream protein analyses. 

Meanwhile, researchers from Nanjing University demonstrated the efficacy of anti-CD4 trimeric VHH antibodies in inhibiting HIV-1 infection by inducing CD4 conformational alteration. CD4, pivotal for HIV-1 entry, poses challenges for drug development due to neutralization and cytotoxicity concerns. Strikingly, engineered trimeric Nb457 nanobodies achieve complete inhibition against live HIV-1, outperforming Ibalizumab and parental Nb457, and shows therapeutic efficacy in humanized female mouse models. These findings highlight anti-CD4 nanobodies as promising HIV-1 therapeutics, with potential implications for advancing clinical treatment against this global health challenge. 

Besides HIV-1, scientists from New York University Abu Dhabi have designed nanobodies against SARS-CoV-2 non-structural protein Nsp9, which is required for viral genome replication. One of these anti-Nsp9 nanobodies, 2NSP23, was encapsulated into lipid nanoparticles (LNP) as mRNA. Their observations indicate that LNP-mRNA-2NSP23 is internalized and following translation, it inhibits viral replication by targeting Nsp9 in living cells. Therefore, it may be translated into an innovative strategy to generate novel antiviral drugs highly efficient across coronaviruses. 

This week in the diagnostics field, researchers from The University of Michigan Medical School developed a general method to screen nanobodies for cytochrome P450 enzymes from a yeast surface display library. Substitution of tight biotin-streptavidin binding for conventional primary and secondary antibodies allowed for a reduced screening cost and no further modification of protein. In the case of CYP102A1, they identified specific nanobodies that inhibit the catalytic activity with sub-micromolar affinity that may be useful for investigating the structure and function of P450 catalysis.