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Overcoming Challenges in Developing Antibody Drugs Against Immune Check Point Targets

In May, Dr. Jing Li, Vice President of WuXi Biologics, presented to approximately 175 attendees at the Cambridge Healthtech Institute’s (CHI) 11th Annual PEGS Essential Protein Engineering Summit at the Seaport World Trade Center in Boston, MA. This week we sat down with Jing to continue the discussion on the topic of overcoming challenges in developing antibody drugs against immune check point targets.

Can you elaborate on the mechanisms and functions of immune check-point elements?

Jing: The immune system is a very complex way to protect our body from foreign attack caused by bacteria or virus, as well as to monitor and clean our internal system (e.g,. cleaning and removing apoptotic tissue or tumor cells).  The delicate balance between activation and inhibition of the immune system is tightly regulated by the communications among various immune cells.  One such crucial communication system is the immune check-point system which utilizes multiple receptors and ligands expressed on various immune cells.  In order to easily understand the roles or functions of the immune check-point elements, let’s imagine the immune system is like a car.  One group of immune check-points elements are the “gas pedals” and the other group of immune check-point elements are the “brakes”.  These elements work together to fine-tune immune responses in order to provide an adequate immune response to a target.  Meanwhile, the elements also work together to avoid autoimmunity and the destructive effects of an excessive inflammatory response.  However, it is also well established that tumors use several mechanisms to avoid elimination by the immune system and one of those involves “hijacking” or controlling these check-point pathways.

Given such complexity to the problem, why is there such a large interest in immune check-point targets?

Jing: Immune check-point therapy utilizes monoclonal antibodies to release the “brakes” or to activate the “gas pedals” on suppressed T cells, allowing them to be activated and recover their antitumor activity.  This therapeutic approach has revolutionized cancer immunotherapy.  The extraordinary increases in overall survival of human cancer patients have been noted against two immune check-point targets CTLA-4 (cytotoxic T lymphocyte-associated protein 4) and anti-PD-1 (programmed cell death receptor-1) in melanoma and other malignancies.  The approval of anti-CTLA-4 antibody, Ipilimumab (BMS), and the recent approvals of two anti-PD-1 antibodies, Pembrolizumab (Merck)  and Nivolumab (BMS), have greatly attracted more attention to the immune check-point therapy field.

This is exciting for the field of oncology, are antibodies to these immune check-point inhibitors the answer and if so, how do we generate such drug candidates?

Jing: Antibodies are ideal because they can be engineered to be highly specific, stable, easy to manufacture, well-tolerated in vivo and with high affinity to the target of interest.  There are several approaches to generate antibody therapeutic candidates.  The classic approach is to immunize rodents to generate rodent hybridoma clones expressing functional antibodies. Since the rodent generated antibodies will not be recognized as “self” in the human body and thus may be cleared quickly from the body or cause immune damage due to its immunogenicity, this approach has to be followed by further antibody engineering called humanization to reduce the immunogenicity of the original parental rodent antibodies. This approach has been successfully run for many projects in our group. Alternatively, we can generate hybridoma cell clones expressing fully human antibodies using OMT rats, which are transgenic rats expressing only the human antibody repertoire.  We have formed a strategic partnership with OMT, which de facto gives us the exclusive status of using OMT transgenic rodents in China.  The third approach is to screen for therapeutic candidates from human antibody libraries. The candidates from these libraries are fully human antibodies as well. We have established our own internal proprietary human antibody libraries, and they are ready for use in drug discovery.

What would be the special challenge in developing therapeutic antibodies against immune check-point targets?

Jing: One critical step in drug discovery and development is to test your therapeutic candidates in certain disease relevant animal models to verify your therapeutic rational and test the efficacy of your therapeutic candidates.  The commonly used preclinical animal models for cancer drug discovery are xenograft mouse models, which are mice implanted with human cancer cells.  However, the cancer immune therapy needs to leverage the inherent mouse immune system to exert its anti-tumor activities.  The immune system and tumor in the animal models have to be in the same immune background.  So the conventional xenograft mouse models may not fit immune therapy drug discovery.  The syngenic mouse tumor models, in which the syngenic mouse tumor cells are implanted in mice, have to be used. This will require your therapeutic antibody candidates to cross-react to mouse targets in such syngenic mouse tumor models. The general protein sequence homology between human and mouse species for those known immune check-point targets is pretty low, posing significant challenge on generating such cross-reactive antibody drug candidates for preclinical in vivo testing.

What would be the solution and how easy is that to do?

Jing: We need to carefully design our work flow of antibody generation to maximize our chance to achieve the same human and mouse target cross reactivity.  As you can imagine, with such low target protein sequence homology between human and mouse species, to develop a therapeutic monoclonal antibody that has high affinity for both the human and mouse target, is also highly specific, efficacious, soluble, and stable and can be manufactured easily is not trivial.  All of these selection criteria I’ve just mentioned make finding the ideal antibody candidate for clinical trials a real challenge.  Using these various selection criteria, we must screen thousands of antibodies just in the hope of finding 3-5 ideal therapeutic candidates.  In case we cannot find a good candidate which can cross-react with both the human and mouse target with equal activities, we have to initiate a parallel program to generate a surrogate antibody which recognizes the mouse target, for the purpose of verifying the therapeutic rational in preclinical animal models.  Both the human therapeutic antibody and the mouse surrogate antibody must be well-characterized and perform similarly in vitro. This requires though a very experienced team like we have at WuXi  to generate and characterize these complex biological molecules.

In your talk you mentioned the using multiple discovery platforms – why would you need to do that?

Jing: There are many different antibody discovery platforms and technologies that allow you to screen thousands of antibodies.  However, each of those platforms has its own unique strengths and weaknesses.  We’ve seen time and time again in the industry that relying on one platform may not generate the ideal antibody candidate that you’d like to take into clinical trials.  The strategy of “multiple shots on goal” has been adopted by many big pharma companies when they work on high value targets.  Thus, to overcome the challenge, to maximize your chance of success, and to expedite the drug discovery process, we’ve developed multiple different technology platforms to greatly increase the likelihood of finding the best therapeutic candidate.  You hopefully will not need to use all of them but I showed data in my talk in Boston how utilizing two of our platforms doubled the number of ideal mAb therapeutic candidates.  We were thus able to provide our clients more timely solutions or better candidates to their drug discovery problems.

Can all the work you mentioned be performed at WuXi?

Jing: Yes, that is what makes WuXi so unique.  Our large highly trained antibody discovery team has significant industry experience.  Many of our senior staff have worked in the biologics discovery field in big pharma for 10-20 years.  We also work closely with our colleagues in discovery biology, oncology, cell line engineering and process development to put together unsurpassed capabilities and capacities for our clients.  This single-source approach provides one-stop-shop drug discovery and development services with significant time savings and efficient trouble shooting for our clients.  Thus all the resources they need for their drug discovery and development efforts are right here in Shanghai.

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