Monoclonal antibodies (mAbs) have become the world’s default biological therapeutics, with an industry dedicated to their discovery, development and manufacture that is highly protective of their market dominance. However, VHH proteins backed by new technology are now positioned to challenge their dominance, promising the creation of a new class of medicines that dramatically lower the cost of lifesaving therapies.
What are VHH?
VHH have similarities to traditional IgG (immunoglobulin G) antibodies but are smaller, simpler, and more robust. Originally isolated from Camelidiae (camels, llamas and alpacas) around 25 years ago, these single-domain proteins represent the antigen-binding region, otherwise known as the VH domain, of a heavy chain-only antibody. While VHH are not biosimilars, they can undertake similar roles and offer significant advantages IgG monoclonal antibodies in certain applications.
Therapeutic VHH’s have already been approved by the FDA for human use. Typically, VHH go through a similar development cycle to IgG mAbs, but once QTL technology is applied, their manufacturing costs are significantly lower than those of the monoclonal antibody they are replicating.
CHO is effective but costly
High quality IgG monoclonal antibodies are mostly manufactured by Chinese Hamster Ovary (CHO) cells. This approach is expensive, and the costs do not reduce significantly, even at large scale. Despite this, the high price of IgG monoclonal antibodies while on patent enables attractive margins, and the cost of manufacture is factored into the economics of such projects.
When the patent estate expires on regulated IgG monoclonal antibodies, competition from biosimilars becomes possible. In practice, however, this seldom happens, ensuring that prices remain high. This is bad news for government health agencies and health insurers. It’s also bad news for taxpayers and those who pay the health insurance premiums.
Regulators deter biosimilar competition
The bioequivalence regime of regulators involves the submission of multiple clinical batches to demonstrate that the biosimilar is sufficiently the same as the original reference biological therapeutic. When the batches are made in CHO, the cost of developing a biosimilar goes up significantly, especially when a CDMO is paid to carry out the process. These costs, and the price reduction limitations owing to the ongoing high cost of manufacture, have a real impact on the investment case for such projects, reducing the number of biosimilars that are developed.
From a global perspective, history shows that accessibility to lifesaving medicines can be improved when a biosimilar enters the market because it tends to lower prices and expand supply. But in the IgG monoclonal antibody market, even when a biosimilar is successfully developed, the high cost of manufacturing restricts the scope for cost reductions, preventing prices from falling significantly.
How technology can help
QTL technology allows production strains to be optimised for the manufacture of specific VHH using baker’s yeast to dramatically lower the cost of manufacture. Another advantage of this new approach is that both the VHH and the optimised strains for manufacture are not encumbered by the extensive patent estates of IgG monoclonal antibodies.
VHH can bring advantages of stability, delivery, and tissue penetration that can give them a market advantage over the original reference monoclonal antibody. Where an efficacy mechanism requires multi-valency, IgG monoclonal antibodies have evolved to be bivalent whereas VHH can readily cope with multi-valent mechanisms, opening the possibility of delivering improvements in efficacy compared to the reference molecule.
Disruptive potential
QTL technology promises to unlock the full power of VHH as a more affordable and accessible biological therapeutic class, with arguably more disruptive potential than biosimilars. They can be developed to enter markets where IgG monoclonal antibodies still have years of patent protection remaining. In many cases, they will match or outperform the efficacy, convenience, and safety of the reference product in therapeutic areas where IgG monoclonal antibodies are currently the leading medicines.
