Introduction

Antibodies are proteins naturally produced by human body. They are Y-shaped, with two ends being identical and able to recognize and bind to objects which are external to our body (some "invaders" such as viruses for instance). The third end of the antibody is able to "call and bring" immune cells to them, in order for them to destroy the invader. But antibodies are also able to recognise and bind to cancer cells.
This latter ability can be further expoited. Indeed, toxic drugs which are used to fight cancer are able to destroy cancer cells, but they can also destroy healthy cells, inducing secondary effects. A way to reduce these side effects is to specifically adress the drug to cancer cells, by attaching the drug to a chemical vehicle that will "drive" the drug to the cancer cell.
Hence, one of the recent approach to fight cancer is to attach a drug to an antibody that specifically recognise cancer cells and will be able to transport the drug to them and spare a maximum of healthy cells. This technology is called antibody-drug conjugates (ADC).

 

 

Now, the question is – how do we attach drugs on the antibody?
Indeed, an antibody is a protein, that is to say a big chemical structure made of hundreads of small molecules (called amino acids). The amino acids constituting the antibody possess chemical functions - that we could imagine as being “chemical hooks” - which are accessible at the surface of the antibody. Organic chemistry reactions allow researchers to “attach” interesting objects (“active species”), such as drugs, to these hooks and hence to the antibody. However, if this approach gave interesting results, antibodies possess on their surface a multitude of identical hooks. As a consequence, it is very complicated to have a perfect control on the number and location of the active species being attached to the antibody. To stand for this issue, let’s imagine that we make 10 experiments with 10 different persons. In each experiment, we give 3 identical keys to the person. Each key allows to open each one of the 5 doors surrounding them. If I ask the person to open 3 of the 5 doors, there is only little chance that the 10 persons chose exactly the same 3 doors in each experiment.
Concretely, when active species are attached to the antibody, if the aim is to attach only two elements per antibody, it will rather ends up with a statistical distribution of antibodies having 0 or 1 or 2 or 3 or 4 elements attached.

 

Issue being addressed

The lack of control on the number of active species per antibody is problematic regarding multiple aspects: 1. The optimal ratio of active compound per antibody can vary depending on the type of compound and type of disease to treat. 2. If an antibody-drug conjugate treatment gives good results against a cancer, if this treatment is actually a mixture of antibodies with various number of drug attached to it, it will be impossible to determine if some antibody-drug conjugates among this mixture has an optimal antibody/drug ratio and thus a better activity than others, or if having a mixture of different species is actually better. 3. Regarding security/validation of production process, it is better to have the most homogenous mixture possible. Ideally, only one drug/antibody ratio should be obtained. 4. New treatments developed consist in attaching different types of active compounds or drug on the antibody, in order to get a synergistic effect (in other word, to attack the cancer through different fronts to improve the chances to destroy it). Attaching two different drugs on the antibody faces the same issues as those described so far (points 1 to 3) but difficulty is improved.

On another hand, “bispefic antibodies” are a new sort of antibody, able to recognise two different targets. They are kind of a “mix” between two antibodies. Their capacity to act simultaneously on two different targets is very useful for cancer treatment, but they are made through bioengineering: To simplify, a complex “chemical notice” is created and given to enzymes so that they can read it and produce the bispecific antibody. But the process is long, complex and time-consuming, especially when a lot of different bispecific antibodies are meant to be evaluated (this is called a “screening”). Thus, a faster method to create bispecific antibodies, even in low quantity, would be helpful to ease and speed up screening processes.

 

Why is it important for society?

For all these reasons, developing chemical methods that allow to attach active compounds on the antibody with a perfect control is of huge importance. On a long term view, this should allow to develop optimised treatments (through optimised drug/antibody ratios) and then benefit patients.
Regarding the easier and faster generation of bispecific antibodies, this could highly improve the number of bispecific antibodies evaluated in research lab and clinical trial, thus speeding up the finding of new treatments.

 

The overall objectives

1. To develop a method that allows generation of antibodies with active compounds (such as drugs) attached to them in a very control manner. Notably, having access to various and rare drug/antibody ratios (e.g ratio of 1, 2 or 3) with a same generic method is a pursued goal.
2. To develop a method that allows generation of antibodies with different active compounds (such as two different drugs) attached to them in a very control manner.
3. To develop a fast and generic method to generate bispecific antibodies without using bioengineering, but rather using chemical reactions.