Small antibodies with big implications

Tiny molecules derived from the blood of camels and llamas hold the potential to transform the treatment of patients across multiple therapeutic fields and indications. These small, highly specific antibodies can target disease-related proteins, potentially redefining treatment strategies. Given its potential, Octapharma is pioneering in the field and investing in this promising and rapidly expanding area of research.

“The discovery of what we now know as ‘VHH antibodies’ (which are often referred to as ‘nanobodies®’*) is a remarkable example of serendipity in science,” says Thomas Güttler, who leads the Octapharma Recombinant R&D team in Heidelberg, Germany. With VHH antibody technology at the heart of his department’s focus, the team is pioneering innovative biologics across critical care, haematology, immunotherapy, and beyond – addressing unmet medical needs with breakthrough solutions.

^{* NANOBODY® is a registered trademark of Ablynx N.V.}

Serendipity in action

When biology students at the Free University of Brussels stumbled upon a strange antibody pattern in dromedaries during a routine teaching course in the late 1980s, they unknowingly set the stage for one of the most exciting discoveries in antibody science. At the time, their task was simple: isolate antibodies from serum, and classify them into known types.

Concerned about the emerging HIV epidemic, they opted to work with dromedary serum rather than human plasma. What they found was very unexpected – a class of smaller antibodies that defied the understanding of immunologists at the time.

This discovery led to further investigations spearheaded by Cécile Casterman and Raymond Hamers who confirmed that animals in the Camelidae family (which includes camels, llamas, dromedaries and alpacas) naturally produce these unique antibodies which are not just smaller but also simpler than their human counterparts. The molecular portion that makes these “miniature” antibodies bind to their “targets” can be produced independently from the rest of the antibody and is now known as a VHH antibody.

These smaller but potent versions of antibodies, later also found in sharks, bind their targets with remarkable strength and specificity and are highly stable – properties that the immune systems of camelids and sharks naturally develop during an immune response when challenged by pathogens or toxins.

Ethical and potent antibody alternatives

The process of obtaining therapeutic VHH antibodies begins by exposing a camelid to a desired target, such as a plasma protein. This prompts its immune system to produce antibodies directed against that target. “We then isolate the antibody-producing immune cells from a small volume of the animal’s blood and obtain the DNA blueprint for virtually its entire VHH antibody repertoire. Next - in a process dubbed 'lead discovery' - we identify promising candidates for further refinement,” explains Antra Zeltina, who leads the R&D Molecular Design Group at Octapharma.

“Animals are only needed in the very early lead discovery stage, and they are not harmed in the process. It’s merely like getting a vaccination and bloodwork at your doctor’s office,” Antra adds. "Moreover, advanced animal-free, computationally designed VHH antibody repertoires are increasingly being used in our drug discovery workflows."

Throughout lead discovery, VHH antibodies are made in microorganisms such as bacteria or yeast, unlike conventional antibodies which always call for more elaborate mammalian cell cultures. This simplicity gives VHH antibodies decisive advantages in production: they can be manufactured to scale at a fraction of the costs of conventional antibodies. Even when generated in mammalian cells, yields are notably higher with VHH antibody-based molecules.

However, despite their advantages, the diminutive size of VHH antibodies presents a challenge. As Thomas points out, their small format means they quickly clear from the bloodstream and thus have a short half-life of only a couple of hours at most.

Versatility tailored for function

To overcome this limitation, innovations such as protein fusions are used to extend the VHH antibodies’ half-life, making them a scalable and practical solution to the growing demands of healthcare. This highlights how these tiny antibodies can be “mixed and matched” like Lego bricks to achieve desired therapeutic outcomes.

Laboratory and computational techniques, which include cutting-edge machine learning approaches, are used to further enhance VHH antibodies - improving their selectivity, functionality and immunogenicity in the so-called “lead optimisation” process. This careful refinement ensures that VHH antibodies are safe and precisely tailored to their intended therapeutic use in humans.

A leap toward transformative therapeutics

Octapharma's R&D team has made significant strides in both lead discovery and optimisation, demonstrating the transformative potential of VHH antibodies. These achievements highlight the department’s commitment to pushing the boundaries of this innovative technology and positioning VHH antibodies as a key development in therapeutic research.

"Getting the chance to transform discovery research into groundbreaking therapeutics is a unique privilege," says Thomas. “VHH antibodies hold immense potential, and we are on the verge of fully unlocking their capabilities. As we continue to strengthen the scientific expertise within our department, these innovations will drive significant progress and create exciting new opportunities for future use in patient treatments.”