Monoclonal antibodies look at the target, double antibodies look at the platform——Analysis of Amgen, Sanofi, and Roche's double antibody platforms

Wen|Truto

In recent years, against the background of the global wave of innovation, global pharmaceutical companies have continued to introduce new innovations in the field of cancer treatment.

Although there are precedents for successful marketing of double-antibody drugs, their development is by no means an easy task.

01.

Figure: IgG-like double antibodies with Fc region and non-IgG-like double antibodies without Fc region

(1) IgG-like double antibody with Fc region: Fc fragment is the basic structural unit that exists in natural antibody molecules.

The IgG-like double antibody with the Fc region has many advantages, which are closely related to the Fc region in the molecular structure, including long half-life (recycling effect of FcRn), efficient separation and purification (thanks to the Fc region Protein A/G The recognition zone) and the ADCC and CDC mediated by the Fc zone.

However, IgG-like double antibodies with Fc region have heavy chain/heavy chain and heavy chain/light chain mismatch problems.

Figure: Light/heavy chain mismatch phenomenon

(2) Non-IgG-like double antibodies that lack the Fc region, that is, double antibody molecules that do not contain the Fc region.

02.

(1) Knob-in-Hole (KiH) platform-to solve the problem of heavy chain/heavy chain mismatch

KiH was invented by the Genentech team and is the most basic platform to solve the problem of heavy chain/heavy chain mismatch.

In short, a small amino acid is used to replace a large amino acid in one heavy chain to form a "Hole", and a large amino acid is used to replace a small amino acid in the other heavy chain to form a "Knob", and finally the formation of heterodimerization is guided by the electrostatic orientation theory.

Figure: KIH structure

Source: Roche

(2) CrossMab platform-solve the problem of heavy chain/light chain mismatch

CrossMab achieves the purpose of preventing mismatches by swapping the regions of the heavy and light chains of one of the antibodies.

(3) Ybody-introduce scFv to form heterodimer

YBODY is a bi-specific platform developed by Wuhan Youzhiyou Company.

03.

(1) BiTE platform-improve half-life through Fc fusion

BiTE (Bispecific T-cell Engager) was developed by German Micromet company.
In 2012, Micromet was acquired by Amgen, which acquired BiTE technology.
Blincyto is a dual-antibody drug developed based on the BiTE platform.
It will be launched in China in December 2020, and BeiGene has Chinese rights and interests.

BiTE is a tandem scFv, which is a series of scFv binding T cell antigen CD3 and tumor antigen binding scFv, which can simultaneously bind T cells and tumor cells and induce T cells to target and kill tumor cells.
In response to the short half-life problem, Amgen designed a half-life extended (HLE) BiTE molecule, which converts non-IgG-like double antibody molecules without Fc ends into double antibody molecules with Fc ends, increases the molecular weight of the double antibodies and uses FcRn to recycle.
, Extending the half-life of the drug.

Figure: HLE BiTE molecular structure diagram

Source: Amgen

(2) Bi-Nanobody platform-prolong the half-life through albumin fusion

Nanobody contains only one heavy chain variable region (VHH) and two conventional CH2 and CH3 regions.
Compared with traditional antibodies, Nanobody has the advantages of small molecular weight, simple structure, strong tissue penetration, and can penetrate the blood-brain barrier; it is not easy to stick and aggregate, but has the shortcoming of short half-life.

In response to the short half-life problem, Ablynx (acquired by Sanofi in 2018)’s exclusive half-life extension technology combines Nanobody with serum albumin to increase the molecular weight of the bi-antibody and use the recirculation effect of FcRn to extend the half-life from several hours to More than 3 weeks.

Figure: Schematic diagram of Nanobody and albumin binding

Source: Ablynx