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Anonymous Jan 08

Combination Therapy is the Future of Immuno-onclogy

Combination Therapy is the Future of Immuno-onclogy

Tony joined Ablynx as Chief Scientific Officer in October 2013. In this role, he leads the company’s discovery, pharmacology, and CMC organisation. Tony has more than 15 years of biotech R&D experience and expertise in building out pipelines and expanding platform technologies

Phacilitate: After a decade of disappointing results, immunotherapy has finally been recognised as a treatment that can provide a significant clinical benefit. Are we seeing a paradigm shift in the way we approach first-line treatment in cancer?

Dr de Fourgerolles: We are seeing a paradigm shift.  I think with the clinical results and the approval of anti-CTLA4, Yervoy® and now the anti-PD1 antibodies we are seeing real and significant clinical benefit for patients.  This is leading to an explosion of clinical development with these and other immune-oncology drugs.  People are looking at both new cancer indications and exploring combination therapies.  As an example, Merck has gained approval for their anti-PD-1 drug, Keytruda® for the treatment of advanced melanoma and metastatic NSCLC.  Yet, they are currently conducting >160 clinical studies with this drug across more than 30 tumour types as a monotherapy and in combination.  It’s a similar story for the other immunotherapy drugs as well.


Phacilitate: Merck has extended its immuno-oncology pact with Ablynx with the addition of up to 12 new programmes in an alliance potentially worth $4billion. Your company specialises in Nanobodies, a novel class of proprietary therapeutics proteins based on single-domain antibody fragments.  Perhaps you could elaborate more on the action of this novel compound? Why the excitement in your work?

Dr de Fourgerolles: To clarify on the immune-oncology collaboration with Merck & Co., Inc., we have in fact signed two agreements with the initial agreement signed in February 2014 and a subsequent expansion signed in July 2015.  In terms of the scope and progress of the collaboration:

  • targeting multiple immune-checkpoint modulators
  • worth up to $6B in potential future milestones plus royalties.
  • up to 17 Nanobody programmes with a focus on multi-specific combinations
  • first in vivo pre-clinical milestone (nearly $4.0M) was achieved with a bi-specific nanobody in October 2015

The Nanobody® platform consists of single domain antibody fragment, where the entire antigen specificity of a 150 kD antibody is reduced to a single immunoglobulin or VHH domain which is 1/10 the size.  This 15 kD Nanobody can be linked in series (through genetic fusion), with each Nanobody being a different drug, and thereby rapidly enable multi-specific drugs.  Much like a string of pearls or beads on a string, where each pearl or bead can be rapidly interchanged.  The whole approach has been clinically validated now in over 1000 patients using multiple different drugs and different routes of administration, including intravenous, subcutaneous, and inhaled. The most advanced Nanobodies are currently in phase II and phase III clinical trials.

There are multiple reasons why we are particularly excited about this collaboration with Merck.  

  • Firstly, we and the majority of the field believe that combination therapy will be the way forward in immune-oncology.  You can already see that in some of the clinical results where for instance combination of anti-PD1 and anti-CTLA4 gives much higher overall response rates than either therapy alone - 10-20% for monotherapy compared to 30-50% for combination therapy in certain cancers.  Making multi-specific drugs and the ability to rapidly mix and match Nanobodies with different specificities plays to one of the strengths of our platform.  In immune-oncology, there are many different combinations to try and test, and we are able to make Nanobodies to a large panel of potential targets and rapidly turn them into multi-specifics and thereby see which combinations work best.
  • This platform advantage, coupled with the clinical insight that Merck can bring to bear results in a real competitive advantage.  It allows us to bring clinical insights back into drug discovery.  Merck is learning in the clinic what happens when people are treated for instance with anti-PD1 mAb i.e. what is the cellular and target expression profile in those patients who are responders and those who don’t respond and which potential drug targets go up and which go down?  This provides key insight into which combinations might work best.  Obviously, one needs to make these multi-specifics and test them pre-clinically and then clinically.


Phacilitate: Ablynx has achieved pre-clinical proof-of-concept with the nanobody construct. What are the major challenges in developing a selective bi-specific molecule, expected to connect two different immune modulators?

Dr de Fourgerolles: Truthfully, there are relatively few challenges in actually making the drugs. Making bi- and multi-specific Nanobodies is something we have been doing for a very long time to develop drugs for both ourselves and our partners.  We have this process well worked out and optimised.  The real hurdle is having the clinical and biological insight to know which target combinations to pursue and that is where working with a leader in the field like Merck maximises the chance of success.


Phacilitate: 2015 witnessed almost $11 billion worth of I-O deals. How can partnerships push the science in I-O forward and with the talk now all about combination therapies, what are the major challenges for researchers to make these partnerships work?

Dr de Fourgerolles: Merck & Co., Inc. is one of the leaders in the immune-oncology field and they have tremendous expertise in development, pre-clinical and clinical testing of immune-oncology therapeutics. We are the experts in Nanobody drug development. The combination of both companies’ core expertise, intensive interaction and exchange of information and matching corporate cultures are essential to make this partnership a success.  


Phacilitate: With so many experimental therapies being investigated in I-O, what are your thoughts on the challenges of bringing these treatments into the clinic? How are we learning to manage the side effects of the new immunotherapy treatments, for example?

Dr de Fourgerolles: Obviously a lot of energy is being put into the field by multiple companies, and as such progress will be made.  The major challenge from a drug development and partnership perspective is to be able to respond quickly to evolving clinical insights and make the combination therapies that are proving the most successful.  That is where the combination of having a flexible platform for making multi-specifics and real-time clinical insight are key.  As for managing side effects, that is something that clinicians are getting better and better at managing but also something we will learn in parallel as new drugs advance into the clinic.

Interview with Dr Antonin De Fourgerolles CSO, Ablynx