Reviving a Classic Antigen with a Cutting-Edge Approach: Nanobodies for HER2+ Breast Cancer

Abstract

The serendipitous discovery of nanobodies (NBs) around two decades ago opened the door to new possibilities for innovative strategies, particularly in cancer treatment. These antigen-binding fragments are derived from heavy-chain-only antibodies naturally found in the serum of camelids and sharks. NBs are an appealing agent for the progress of innovative therapeutic strategies because they combine the advantageous assets of smaller molecules and conventional monoclonal antibodies (mAbs). Moreover, the possibility to produce NBs using bacterial systems reduces manufacturing expenses and speeds up the production process, making them a feasible option for the development of new bio-drugs. Several NBs have been developed over the past 10 years and are currently being tested in clinical trials for various human targets. Here, we provide an overview of the notable structural and biochemical characteristics of NBs, particularly in their application against HER2, an extracellular receptor that often gets aberrantly activated during breast cancer tumorigenesis. The focus is on the recent advancements in diagnostic and therapeutic research up to the present date.

Keywords: HER2; breast cancer; nanobody; target therapy.

Figure 1

Different antibody structures. Conventional antibodies comprise two identical heavy and two identical light chains associated with disulfide bridges. The antigen-binding fragment (Fab) contains the single-chain variable fragment (scFv), made up of VH and V_L domains. The Camelidae antibody comprises two identical heavy chains only. The antigen-binding portion is represented by a single variable region or nanobody (VHH).

Figure 2

NBs as targeting moieties in diagnostic and therapeutic applications. (A) VHH domain conjugated with a radioisotope (¹⁸F, ⁶⁸Ga, ^99mTc) for radiation-based diagnostic techniques. (B) VHH domain conjugated with a fluorophore for non-radiation-based diagnostic techniques. (C) Bispecific antibody. (D) VHH conjugated with an albumin-binding domain and a toxin (NB-drug conjugate). (E) VHH domain conjugated with a liposome.