Nature Journal Club

William C. Hwang

Burnham Institute for Medical Research, La Jolla, California

A structural biologist has great expectations for llamas’ small antibodies.

Llamas aren’t just unusual and exotic looking: their antibodies are also a reason for much excitement. Made entirely of heavy chains, they are about half the size of those found in humans and many other vertebrates, which are normally composed of both heavy and light chains. When it comes to therapeutic applications, these larger antibodies are hard to store and deliver. But llama and other camelid antibodies demonstrate superior heat-stability and solubility, without compromising affinity or specificity, making them an attractive alternative.

Robin Weiss of University College London and his colleagues isolated three llama antibodies, known as ‘neutralizing’ antibodies, that can broadly prevent multiple HIV subtypes from infecting cells (A. Forsman et al. J. Virol. 82, 12069–12081; 2008). They began by creating an antibody library from two llamas immunized with the HIV gp120 antigen. To select for neutralizing antibodies, antibodies were raised against one HIV subtype but cross-screened against multiple subtypes. The researchers also included a competitive elution step to select antibodies that can compete with binding by CD4, the primary HIV receptor on human T cells. It remains to be seen how these neutralizing antibodies fare in animal studies and where they bind in atomic detail.

Intriguingly, there have been reports of several potent, broadly neutralizing human antibodies (for example, F10 and CR6261 against influenza’s haemagglutinin) in which only heavy chains are involved in antigen binding — reminiscent of the situation of llama antibodies. These studies corroborate that the heavy chain alone can mediate broad neutralizing activity, and invite speculation that this may be a special strategy engaged by the human immune system to reach cryptic binding sites. Llama antibodies may be even better suited for those hard-to-reach targets.

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