Last month, I was fortunate enough to be able to attend (in person!) and present at the Festival of Biologics European Antibody Congress (9-11 November, 2021) in Basel, Switzerland. The Festival of Biologics is an annual conference, which brings together researchers from industry and academia. It was an excellent opportunity to learn about exciting research and meet people working in the antibody development field.
Here are some of my highlights from the European Antibody Congress, with a focus on antibody design and engineering:
1. Roundtable: Applying AI & ML to Protein Development
The roundtables, held on the morning of the first day, were an excellent way to meet people and stimulate interesting discussions at the start of the conference. I (unsurprisingly) attended the roundtable on using machine learning in protein design. We discussed various important challenges in the field from model architectures (e.g., transformers and graph neural networks) to data (how much and how diverse data is needed for a target-specific application?). Another open question is the approach for future ML-based antibody design: de novo design of or optimising natural repertoire antibody sequences.
2. Bi-specifics
As has been apparent for a few years, the biologic therapeutics field is moving towards alternative antibody formats (for a wide range of examples, check out my previous blog post). At the forefront of these alternative formats are bispecific antibodies (bsAbs), which have the ability to bind two different target sites, either two antigens or two epitopes on one antigen. A range of talks and panels highlighted the applications of bi-specifics including as T cell engagers for treating cancers.
One bsAb example presented at the conference by Prof Harald Kolmar, was an engineered molecule for treating colorectal cancer (CRC). This bsAb binds CEACAM5 (a CRC marker which can be shed by tumour cells and promote metastasis) to facilitate its clearance, as well as cell surface-bound CEACAM6 to target the antibody to the cell surface [1].
3. On/off switches
Antibody engineering is being taken further than just adding more binding sites, including by designing on/off switches to mediate antibody binding activity. There are a range of potential stimuli (Figure 1), with two addressed at the conference being pH-dependency and protease masking.
The two arms of the CEACAM5/6-binding bsAb described above not only bind different antigens, but one is pH-dependent while the other is not [1]. This confers further important capabilities, by promoting CEACAM5 recycling: the bsAb binds soluble CEACAM5, is taken into the cell via endocytosis and detaches from CEACAM5 in a pH-dependent manner in the endosome (upon which CEACAM5 is degraded in the lysosome). The bsAb is recycled in a FcRn-dependent manner.
In a different approach, Benjamí Oller-Salvia’s group are designing a protease-masked antibody, which is activated in a tumour environment: the antibody binding site is capped by a masking moiety, which is connected to the antibody via a linker with a cleavage site for a tumour-specific protease. This protease cleaves the masking moiety in the tumour environment, exposing the antibody binding site to mediate its functions (Figure 2).
4. Broadly-neutralising antibodies
Broadly-neutralising antibodies are of great interest, as they would be able to protect against multiple, for example, infectious diseases or different mutants of a virus. In another application, such cross-reactive antibodies are being developed as antivenoms against snake venoms in the Tropical Pharmacology Lab, Technical University of Denmark. Strategies members of the group, including Prof Timothy Jenkins, discussed at the conference were (1) conducting phage display with cross-panning and (2) generating a ‘consensus’ venom (from an amalgamation of the sequences of multiple venoms).
In all, this was a fantastic experience and I am so glad I had the opportunity to attend in person! Thank you very much to the organisers for the opportunity to present my work.
References
[1] Bogen JP, Hinz SC, Grzeschik J, Ebenig A, Krah S, Zielonka S and Kolmar H (2019) Dual Function pH Responsive Bispecific Antibodies for Tumor Targeting and Antigen Depletion in Plasma. Front. Immunol. 10:1892. doi: 10.3389/fimmu.2019.01892
[2] Lucchi R, Bentanachs J, and Oller-Salvia B (2021) The Masking Game: Design of Activatable Antibodies and Mimetics for Selective Therapeutics and Cell Control. ACS Cent. Sci. https://doi.org/10.1021/acscentsci.0c01448
