CEO Perspective: Dr. Peter Pack, Crescendo Biologics
Perspectives from Leaders in Immuno-Oncology
Crescendo Biologics has established a leadership position in the development of human VH therapeutics. Crescendo’s Humabodies combine a VH fragment format of minimal size with the power of transgenic mouse technology – the gold standard in antibody therapeutics development – which confers the substantial benefits of in vivo maturation. Humabodies have excellent potency and druggability, are 100% human and represent the smallest possible immunoglobulin, offering a range of plug & play options for generating novel multi-specific biologics. Humabodies therefore have the potential to establish a valuable new class of therapeutics.
Crescendo is now expanding its oncology pipeline with a range of VH Product Building Blocks for novel multi-specific Humabodies targeting a range of cancer indications where Humabodies have the potential to deliver high-value therapeutics to patients.
In February Coulter:Pulse took a trip to Cambridge to interview Dr. Peter Pack, CEO of Crescendo Biologics:
Coulter:Pulse – What defining moments in your own career led you to this exciting point, leading Crescendo’s strategy in the field of Immuno-Oncology?
Dr. Pack: If we go back to the start, I was never really your typical scientist. I studied chemistry, yes, but my family background played a huge role in who I am. My dad is an architect and the family business was always the main topic at home. Customers (and the challenges that come with them) were central and for me that was always “normal”. The MorphoSys founders hired me during incorporation of the company for the innovative ideas in my PhD thesis, but when I started working, my co-scientists didn’t have quite the same focus as me. They would not pick up a phone even when I pointed out this could be our first customer. That was really the moment I realised I didn’t fit the typical mould!
After witnessing MorphoSys’ IPO as a Director R&D, I knew I had to emulate that – as a CEO or founder in my own right. I started mtm laboratories in Heidelberg as a Biomarker company in 1999 and built it over 10 years into a fully integrated Cancer Diagnostics company with subsidiaries in 5 countries, marketing our own pipeline in women’s health. This was one of very few German Biotechs who made it to the market with its own products and revenues. MorphoSys continued to grow in the meantime – with 25 products now in the clinic and several hundred people – success based on a library of technology that I had initially developed with two colleagues! I was co-inventor of the most commercially successful antibody phage library, founded in 93/94 – and this is still a force some 20 years on. And MorphoSys remains one of the 3 most successful Biotechs in Germany even now, still using the original concept.
Then followed five years running marketing and sales companies that were extremely profitable – success was no longer based on IP, patents and future promise but on turnover and costs. It surprisingly turned out that many doctors and clinicians were less interested in innovation for their patients and more interested in their personal revenues! I learnt a great deal more about markets and the definition of product success – a product needed to do its job and meet the needs of the customer.
In retrospect, I played an instrumental role in companies that were either successfully sold (mtm laboratories, Polytech Ophthalmologie, Signature Diagnostics), highly profitable (LGC Standards, Polytech) and/or went public (Morphosys AG). Raising investment and being involved in different kinds of exits was a very exciting time – Morphosys was the first German IPO of a biotech company and attracted a great deal of interest from the national and international media.
You could say I now have a holistic perspective, as I can also draw on some VC experience. Priorities there differ once again. Many investors are not really interested in whether a product ever reaches the market. They want to get in early and get out at the optimum time. When companies are sold, many of the developed technologies are not adopted or the products don’t make it to market. For me, then, the pragmatic solution is always the best one…don’t overdesign but go for a compromise. The success story is not always the fanciest, newest, shiniest idea. It has to be state-of-the-art but also robust, work reliably and be produced at a reasonable cost.
The beauty of Crescendo Biologics is the brilliance of its transgenic mouse platform – a well-advanced but also robust technology that works. And it is not only robust; it is also state-of-the-art. Many years had been spent perfecting it before I started as CEO last summer. I initially came to Crescendo as an investor, having realized what leads and potential product candidates it would have based on my initial background in antibody engineering. Hugely impressed with the building blocks coming straight out of the mouse and its plug & play characteristics, I was convinced we had a world of opportunity ahead. Crescendo’s Humabody platform has the efficacy of other antibody solutions but can be produced in much bigger volumes and much more quickly. Plug & Play to formatted, multi-specific constructs is much easier and more straight-forward than that of most competitors.
Coulter: Pulse – Please can you tell us more about Crescendo’s technology, your recent transition and what plans you have in the Immuno-oncology arena?
Dr. Pack: Crescendo is building a pipeline of new differentiated medicines, including Humabody™ Drug Conjugates (HDCs) and multi-specific immuno-oncology (IO) modulators, through in-house development and strategic partnerships. Last year’s transition to a product-oriented oncology therapeutics company is a pivotal moment in Crescendo’s corporate development.
The Crescendo pipeline comprises two main components:
Humabody™ Drug Conjugates (HDCs)
Humabodies are the smallest antibody fragments (12kD which is 1/10 of a conventional antibody) and show rapid, affinity-driven penetration of solid tumours and fast clearance from systemic circulation as we could recently demonstrate also in vivo. This results in a high tumour-to-blood ratio and reduced systemic toxicity, thereby enhancing therapeutic index and facilitating continuous high dosing. Systemic availability and accumulation in tumours can be enhanced by a tunable half-life extension.
Multispecific Immune Checkpoint Modulators
Immune checkpoint modulators have been identified as a highly promising target class for new cancer immunotherapeutics. Crescendo is developing multivalent and multi-specific product candidates with wide potential applicability across oncology indications. The goal is to leverage the advantages of the modular Humabody™ approach and Crescendo’s expertise in engineering products to create product candidates aimed at re-engaging the body’s immune system to recognise and destroy cancer cells.
There has been plenty of success with conventional antibodies in the past but the future is in multi-specific products. The huge structure of monoclonal antibodies and long systemic half-life means they are sub-ideal for this purpose. What will be in the clinic in 5 years will be much more tailored and optimised.
Pharmaceutical companies are happy with our concept of taking just the tip of the antibody molecule because
- it is still the (essential) part of a familiar larger protein
- it is 100% human
- it is in-vivo matured in contrast to pure phage display approaches
- it is more robust and heat-stable than alternative fragment approaches
Coulter: Pulse – How is Crescendo’s particular approach differentiated from that of other players in IO?
Dr. Pack: Compared with monoclonal antibodies, Humabodies offer a unique combination of potential benefits that results from their small size, cost-effective production and modular plug & play engineering options for generating novel bi- or multi-specific formats.
Humabody Drug Conjugates (HDCs) are very small, robust molecules with a well-defined DAR and tunable serum half-life. The latest data shows that they could realistically represent the next generation of targeted drug conjugate therapies, with the potential of remedying the key deficiencies associated with current ADCs in the clinic, i.e. their non-ideal therapeutic window
Treatment of solid tumours still represents an area of great unmet need. However, the excellent characteristics of HDCs will enable us to deliver superior therapeutic benefit by using a ‘dose high, hit hard and leave’ approach, thereby reducing any undesirable side effects.
Coulter: Pulse – As a CEO in this competitive and rapidly evolving arena, what do you see currently as your main challenges?
Dr. Pack: With actually too many product opportunities open to us, we now have to refine our goals and develop those products with the most potential. The challenge is to select the best bi- and multi-specific combinations for in vitro testing from hundreds of potential candidates. Then a hybrid business model will enable us to develop some products in-house while others are developed by our partners in parallel.
Coulter: Pulse – Which do you see as the key future developments in Immuno-oncology?
Dr. Pack: Combination therapy approaches and multi-specific products are the future. Picking and choosing from different mechanisms to achieve multi-specificity with additional, synergistic effects. Targeting different mechanisms in oncology with the same molecule. One fit-for-purpose molecule using the rapidly growing number of building blocks we have now. Response rates among cancer patients are improving all the time – a 20% response with a monospecific checkpoint inhibitor has now become 50% by targeting two IO targets at the same time, because of the synergistic effects.
Crescendo’s in vivo maturation technology for 100% human VHs with excellent affinities, expression yields and plug & play options is superior to anything that has been done before. We plan to advance the development of new and innovative multi-specific compounds in the area of oncology including immuno-oncology, the new primary focus of the work at Crescendo. We intend to rapidly expand our internal oncology programmes on checkpoint modulators and HDCs, which are a novel alternative to antibody drug conjugates with a better therapeutic window.
Coulter: Pulse – How important is the “human element”– i.e. the right talent – in driving your programme forward?
Dr. Pack: Most scientists in biotech are first and foremost academics, so we need to convert thinking and become more product- and customer focused. An entrepreneurial mind-set is also critical, something that in the US seems to come more naturally than in Europe, although of course there have been many fantastic success stories in the UK and more than in Germany.
In the extremely competitive immuno-oncology landscape, attracting the right talent is about leadership vision, the right investment and partnership money and being at the cutting edge with technology. Company image is also paramount. Crescendo Biologics has something quite unique in its Humabody platform. Something to really get excited and shout about, not only for the science but also for commercial opportunities.
Add to this the attraction of Cambridge as the UK centre of excellence which pioneered antibody drug discovery, and there are compelling reasons for the very best specialists in the field to want to get involved in the multi-specific constructs of the future.
What keeps me interested is of course the strength of the scientific ideas, but I try not to get lost in the detail. Commercial opportunities and considerations remain critical to our future success.