Of Mice and mAbs: Dr. Larry Green, Ablexis

Ablexis (San Diego, CA) licenses the AlivaMab Mouse, a transgenic mouse that “dramatically improves upon other antibody discovery platforms”. A majority of the world’s top-15 pharmaceutical companies have licensed and use AlivaMab Mouse for antibody drug discovery at more than a dozen sites around the world.

Larry Green-CEO and founder of Ablexis, and co-inventor of the AlivaMab Mouse- is an inventor on several dozen patents covering immunoglobulin transgenic mice and therapeutic antibodies. He received his Ph.D. in Molecular and Cellular Biology from the University of Wisconsin-Madison and did postdoctoral research at the University of Colorado at Boulder and Stanford University.

Joining Aliva Biopharmaceuticals, Inc. in 2008 as CEO, he optimized the blueprint for AlivaMab Mouse and procured a Series A financing, resulting in the founding of Ablexis, LLC in 2009.

Here, Dr. Green talks to Pharm Exec about the evolution of Ablixis and the main challenges associated with the pre-clinical discovery of monoclonal antibodies (mAbs).

PharmExec: Can you outline your background and the development of Ablexis?

Larry Green

Larry Green: I have over 25 years of experience in building and using transgenic platforms for antibody drug discovery. I am an inventor of the XenoMouse® technology and a founding scientist of Abgenix, Inc., which was acquired by Amgen for $2.2 billion in 2006. I had various roles of increasing responsibility at Abgenix, rising from entry-level scientist to a VP-level position. I was fortunate to work with very talented and very smart people from whom I learned a lot about the technologies and the business of antibody drug discovery and development. Also, as head of research collaborations and participating on joint steering committees with our partners that included Abbott (now AbbVie), Amgen, AstraZeneca and Pfizer, it felt like I was inside those organizations too, learning from their scientists, clinicians and business people about how pharmaceutical companies conduct the science and business of antibody drug discovery and development.  I am proud that the work I did at Abgenix has produced dozens of antibodies that entered clinical development and six approved drugs, so far.

I was a founder of Ablexis, LLC in 2009. We established the unique Ablexis-Pharma Consortium business model, which provided Ablexis with non-dilutive operating capital from the five pharmas in the consortium via their upfront payments and then an eight-figure back-end payment when we delivered the fully validated AlivaMab Mouse technology in 2014. Third Rock Ventures and Pfizer Venture Investments were in the Series A, our only financing round. The investors were attracted by the unique model that provided liquidity and had confidence in our plan based on the strength of the leadership team and our vision for the AlivaMab Mouse platform. After delivering the mice to our five pharma consortium members, we proceeded to license the AlivaMab Mouse to other top 15 pharmas, providing a well above-average ROI for our investors. Now a majority of top 15 pharmas, including AbbVie, Boehringer Ingelheim, Janssen, MedImmune, Novartis, and Pfizer, are using AlivaMab Mouse, as well as several other smaller companies. With the acquisition of Ablexis by Deerfield Management, I am looking forward to expanding availability of AlivaMab Mouse through more flexible licensing terms.

What are the main challenges in pre-clinical discovery of monoclonal antibodies and when are they best addressed?

Pre-clinical discovery of good therapeutic antibody candidates should account for both near-term and longer-term challenges in drug discovery and development, taking a long view far beyond just finding an antibody that modulates the target in the desired manner. It is very important to have a well-reasoned target product profile (TPP), which acts as a roadmap and go/no-go decision guide. Elements of a good TPP would include not only the potency requirement for a lead candidate’s modulation of the target but also the “need-to-haves” and the “nice-to-haves” with regard to cross-species cross-reactivity for pre-clinical testing, the affinity of the antibody-target binding, its specificity of binding, and, importantly, considerations of the characteristics required for later development, such as manufacturing, safety, dosing, competitive landscape, etc. Some antibody discovery platforms might deliver antibodies that modulate the target but these platforms also introduce liabilities that may not become apparent until years and many millions - tens and even hundreds of millions - of dollars have been spent.

What are the options for producing monoclonal antibodies during discovery?

Today, the options for the discovery of therapeutic antibody fall into two broad buckets, using in vivo systems, such as mice, or using in vitro systems. If normal mice are used then the antibody has to be “humanized” before it can be administered to humans because a mouse antibody will be immunogenic in patients, which can cause loss of efficacy or serious adverse events. If using a transgenic mouse, then fully human, therapeutic-quality antibodies can be readily produced, which speeds the discovery phase and reduces risks in both pre-clinical and clinical development. So, the choice is human antibodies from transgenic mice, humanized antibodies derived from normal mice, or human antibodies from in vitro display platforms. The technical details on these technologies would (and do) fill textbooks. If one looks at data on antibody drug approvals and success rates in transitioning through mid-stage clinical development to market, then transgenic mice outperform in vitro display technologies by over 200%, and transgenic mice outperform humanization by about 150% in success rate in transition from mid-stage clinical development to approval.

What are the key differences between in vitro display platforms and transgenic animals?

A well-performing transgenic animal platform has been genetically engineered so that the natural immune response has been harnessed to produce antibodies comprising human sequence. The best understood and manipulated immune system in lab animals is that of mice so transgenic mice have been and will be the platform of choice for efficient and successful fully human therapeutic antibody discovery. In vitro antibody display platforms were created with the idea that the naturally-evolved process of antibody generation in an animal could be mimicked in plastic dishes. Today, 28 years after the first publications on in vitro antibody display, new platforms are still being launched trying to fix some fundamental issues with such platforms being able to efficiency generate antibody drugs. It is a bit ironic that this year’s Nobel Prize in Chemistry was in part for phage display of peptides and antibodies while this year’s Nobel Prize in Medicine was for immunotherapy of cancer, with such approved immunotherapeutic drugs all starting as antibodies from mice. In other words, it is from mice that all of these breakthrough drugs for patients were generated. Which platform would you choose to discover breakthrough medicines?

What are the advantages of AlivaMab Mouse technology? How was it engineered?

AlivaMab Mouse was designed to be the best platform for both antibody drug discovery and antibody drug development. I had spent a decade at Abgenix working with the XenoMouse platform, and knew its strengths and its weaknesses. By the mid- to late ‘00s, the weaknesses of antibody humanization and in vitro display platforms were becoming more apparent, such weaknesses manifesting across the spectrum from discovery to costly blow-ups in Phase 3 clinical trials. We worked to incorporate all of this know-how into the design of the AlivaMab Mouse, to make a platform that was efficient and successful for drug discovery and that reduced the risks of costly problems later on in development. At the finish of the design, we had a list of features and qualities that we felt would be best realized by using synthetic DNA technologies to make the transgenes. AlivaMab Mouse strains have completely synthetic transgenes comprised of optimally mixed-and-matched human and mouse coding and control sequence, all included on autonomously functioning immunoglobulin loci.  There is no other platform like it.

What is the relationship of Ablexis and AlivaMab Discovery Services?

Ablexis and AlivaMab Discovery Services are two separate companies. AlivaMab Discovery Services provides antibody discovery services leveraging the AlivaMab Mouse platform and the management team’s expertise and hands-on experience in leading and conducting antibody drug discovery and development. We founded AlivaMab Discovery Services as a result of repeatedly hearing the needs of prospective licensees of AlivaMab Mouse who wanted or needed to outsource antibody drug discovery to a scientifically-driven organization led by a team with in-the-trenches experience and real understanding of therapeutic antibody discovery. 

Why would a company choose to license the technology versus using the discovery services?

The AlivaMab Mouse is an efficient and successful platform in use by our licensees at over a dozen sites. That an antibody from AlivaMab Mouse has already entered clinical development after only 3.5 years since the platform was first used by a licensee is a testament to how well the platform performs. Companies having in-house capabilities for immunizing mice, then recovering and interrogating the immune repertoire can still license AlivaMab Mouse and use it in their own labs. However, many prospective licensees either may lack the capabilities for using an in vivo antibody drug discovery platform or may want to outsource the work. For those such companies, there is AlivaMab Discovery Services.