Recently the European Medicines Agency (EMA) Committee on Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending the approval of Cablivi (caplacizumab), a single-domain antibody (sdAb) drug developed by French pharmaceutical giant Sanofi, for the treatment of adult patients with acquired thrombocytopenic purpura (aTTP).

The European Commission (EC) usually adopts the opinion of CHMP when making the final review decision, which means that it is very likely that Cablivi will be granted a listing to benefit European aTTP patients in the next 2-3 months. If approved, Cablivi will be the first sdAb drug listed globally and the first to specifically treat aTTP.

In the United States, the FDA has granted caplacizumab for the treatment of aTTP in July of last year. Sanofi plans to submit to the FDA in late 2018 a biologics license application (BLA) of caplacizumab for aTTP treatment.

aTTP is a life-threatening, autoimmune clotting disorder characterized by the formation of large blood clots in small blood vessels throughout the body, leading to severe thrombocytopenia, tissue ischemia and extensive organ damage, especially to the brain and heart. Currently, no drug has been approved for treatment of aTTP. Despite the standard care regimens, plasma exchange (PEX) and immunosuppressive therapy, patients still face high-risk thrombotic complications, relapses and deaths.

Caplacizumab is a potent and selective bivalent anti-von Willebrand factor (vWF) sdAb that was granted orphan drug status in the United States and the European Union in 2009. Caplacizumab blocks the interaction of the super-large vWF multimer (ULvWF) with platelets and, therefore, has an immediate effect on platelet aggregation and the subsequent formation and accumulation of tiny microclots. In aTTP patients, this tiny blood clot can cause severe thrombocytopenia, tissue ischemia, and organ dysfunction. This immediate effect of caplacizumab can protect the clinical manifestations of disease in aTTP patients while disassembling the underlying disease process.

Mechanism of action of caplacizumab

Fig.1 Mechanism of action of caplacizumab

The efficacy and safety of caplacizumab in the treatment of aTTP has been demonstrated in a phase II clinical study of TITAN and phase III clinical studies in HERCULES. Data from the TITAN study was published in the New England Journal of Medicine in February 2016. Data from HERCULES was also published at the 59th annual American Society of Hematology (ASH) annual meeting in December 2017.

Caplacizumab was developed by Belgian biotech company Ablynx, a global leader in the sdAb field. At the end of January of this year, Sanofi’s $4.8 billion acquisition of Ablynx resulted in the acquisition of the core product caplacizumab and the respiratory syncytial virus (RSV) sdAb ALX-0171, as well as Ablynx’s potential sdAb platform. It includes 8 new drugs entering the clinical stage and 45 new preclinical drug candidates spanning multiple therapeutic areas, including hematology, inflammation, infectious diseases, autoimmune diseases, and oncology.

About single-domain antibodies

Single-domain antibodies (sdAbs) are a novel class of proprietary therapeutic antibody fragments that contain the unique structural and functional properties of naturally-occurring heavy chain only antibodies. sdAbs can be obtained by immunization of dromedaries, camels, llamas, alpacas or sharks with the desired antigen and subsequent isolation of the mRNA coding for heavy-chain antibodies. By reverse transcription and polymerase chain reaction, a gene library of sdAbs containing several million clones is produced. Screening techniques like phage display and ribosome display help to identify the clones binding the antigen. Alternatively, sdAbs can be made from common murine or human IgG with four chains. The process is similar, comprising gene libraries from immunized or naïve donors and display techniques for identification of the most specific antigens.

Nanobody

Fig.2 Conventional and single-domain antibodies

These heavy-chain only antibodies contain a single variable domain(VHH) and two constant domains (CH2, CH3). With a molecular weight of only 12-15 kDa, sdAbs are much smaller than common antibodies (150-160 kDa) which are composed of two heavy protein chains and two light chains, and even smaller than Fab fragments (~50 kDa, one light chain and half a heavy chain) and single-chain variable fragments (~25 kDa, two variable domains, one from a light and one from a heavy chain). The cloned and isolated single variable domains have full antigen binding capacity and are very stable. These single variable domains, with their unique structural and functional properties, form the basis of the new generation of therapeutic molecule. Due to their small size and unique structure, sdAbs are ideal building blocks for the generation of novel biological drugs with multiple competitive advantages over other therapeutic molecules.