4A Insights‎ > ‎

2013.03.05 The buzz on therapeutic antibodies

posted Mar 5, 2013, 2:46 PM by Sirid Kellermann   [ updated Nov 15, 2013, 10:11 AM ]

4th & Aspen recently attended the Keystone Symposium on "Antibodies as Drugs" in Vancouver, BC. Here are some of the takeaways from this informative meeting (not least of which was that you can buy a hot dog with seaweed on it from a Japadog stand!).
Antibodies as drugs are well-proven and mature. 

With over 30 approved since 1986, and revenues nearing $60B in 2013, antibodies represent a validated approach to the therapy of inflammatory disorders, cancer, and other indications. Antibody-drug conjugates (ADCs) are coming of age, with the approval of Roche/Genentech's Kadcyla (T-DM1) shortly after this conference being the most recent testimonial to the successful introduction of ADCs in cancer immunotherapy. 

The next frontier: greater (tissue) specificity.

Although antibodies are, by nature, extraordinarily specific for their protein target, it's a challenge to identify targets that are solely expressed in diseased tissues and not healthy ones. Overcoming the toxicity caused when ADCs trigger collateral damage in healthy tissues is an area of intense activity. One interesting approach was described by Henry Lowman, CSO and founder of Cytomx, which creates protease-activated antibodies called Probodies™. Here, a linker moiety is attached to a therapeutic antibody, rendering it effectively nonbinding until said linker is cleaved by cell surface proteases known to be overexpressed in diseased tissue.

In addition, there's new developments in the combination of ADCs with kinase inhibitors. Paul Polakis mentioned that researchers at Genentech are leveraging the observation that kinase inhibitors trigger a transcriptional response that upregulates cell surface receptors, making them more receptive to killing by ADCs. Nothing published yet, but we're avidly looking forward to learning more about this approach.
Of mice and camels (or not).

Human antibody-transgenic mice are alive and well, and the reason is in the numbers: A significant proportion of clinically successful therapeutic antibodies are derived from such transgenic mice or from human B cells, likely reflecting the superiority of the natural affinity maturation process (summarized in this concise report by 
David Meininger, Executive Director of Molecular Discovery at Merck (Palo Alto)).
It's been n
early two decades since Abgenix's XenoMouse and Medarex's UltiMab transgenic mice hit the scene, and while both companies have since been respectively acquired 
by Amgen (2006) and
Bristol-Myers Squibb (2009)
, there's no shortage of new alternatives, including Regeneron's VelocImmune mice and Ablexis's AlivaMab mice. Most recently, Crescendo Bioscience introduced the TKO mouse, which generate fully human single domain antibody VH fragments that are much smaller than full-size antibodies and as such have certain desirable characteristics and can bind certain epitopes that  antibodies can't.

Speaking of tiny antibodies, we were surprised by the near non-presence of any discussion of camel antibodies and their derivatives (e.g., Ablynx's nanobodies)monobodies, a binding scaffold based on fibronectin type III domains (FN3), were also MIA. Considering that a number of nanobodies and monobodies are currently in clinical trials in a variety of disease indications, we'd expected more of a presence at this conference.

Molecular engineering is a vibrant area of R&D.

In addition to FN3-based monobodies, there are a number of up-and-coming alternative recognition scaffolds. For example, Molecular Partners' Vice President of Technology Kaspar Binz discussed DARPins (Designed Ankyrin Repeat Proteins), pioneered by Andreas Pluckthün's laboratory at the University of Zürich. DARPins' small size and other biophysical features allow the design, for example, of multi-specific, linked DARPins that can bind several distinct epitopes within the same protein. Binz related how this was being leveraged to target the EGF receptor, a popular cancer target (a 2011 publication elaborates on the EGFR example). The commercial and clinical potential of DARPins has been appreciated by at least one pharma company, Allergan, which did a deal with Molecular Partners late last year focusing on diseases of the eye.

Other multispecific approaches include bi-specific T cell engagers, or BiTEs (technology acquired by Amgen through its 2012 purchase of Micromet and assets including blinatumomab, a BiTE that targets T cells expressing CD3 to malignant B cells bearing CD19). The bispecific approach is also particularly applicable in therapeutic strategies aiming to target heterodimeric surface proteins, with each binding site targeting one of the heterodimer subunits.

A few years ago, several Genentech scientists published an intriguing paper about a "two-in-one" antibody they'd engineered, using Herceptin as a starting point, that was able to recognize not only Her2 but also VEGF. This is notable not only for its protein engineering virtuosity, but also because in a practical sense the concept is similar to that of "dirty" (multi-specific) kinase inhibitors, that may prove to be more effective than single-kinase inhibitors because they target multiple signaling pathways simultaneously. There's been some buzz that the multispecific antibody feat has been replicated elsewhere, but unfortunately, no information was forthcoming at this conference.

Synthetic antibodies and scaffolds represent new ways to design therapeutics entirely computationally, as advocated by David Baker at the University of Washington. While this purely physics-based approach yields scads of potential solutions, it may not be sufficiently high throughput and requires a large amount of computing power. Andy Ellington at the University of Texas-Austin noted that of 100 such solutions screened, only 2-3 have the properties that could make them potential therapeutic candidates. Ellington advocates using high throughput sequencing of antibody complementarity-determining regions (CDRs) derived from a bona fide polyclonal human immune response to inform and 'educate' protein design computational algorithms in order to design better therapeutics more efficiently.

On another matter, it seems that the risk of immunogenicity that occupied a significant part of our own research back in the mid-2000's has been greatly diminished, as computational approaches can essentially 'anti-design' structures to edit out potentially immunogenic sequences.

Technology is only as effective as having the right targets. 

In the end, antibodies and other next-generation targeting strategies are tools whose efficacy is  directly related to the quality of their target(s). We noticed representatives from a number of larger biopharma companies at the meeting who weren't so much there for the antibody technology presentations as they were to scout for new targets and early proof-of-concept data to feed their preclinical pipelines. 

This reinforces our belief at 4th & Aspen that there's a very real demand in the biotherapeutics space not only for new technologies, but also for novel disease-relevant proteins and signaling pathways on which to focus these targeting efforts.