Welcome to Biotechr

Biotechr is written by Dr. Robert Kruse (@RobertLKruse), who holds a PhD and is currently completing his MD. His research work focused on infectious disease and immunology. This blog is focused on analyzing the latest developments in biotechnologies being developed in academia and industry, with a particular focus on biomedical therapeutics. I hope that the posts are interesting and useful, and hope you join in the discussion with guest posts on the site!

Disclaimer: The thoughts on this blog are not intended as any investment advice regarding any companies that might be discussed, and represent my opinion and not the opinions of my employer. This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual.

Monday, June 8, 2015

Thoughts on Seattle Genetics and Unum Therapeutics Deal

by Robert Kruse

The big biotech news of yesterday was a deal struck between Seattle Genetics and Unum Therapeutics to share platform antibodies targeting tumor antigens between the two companies. I wanted to share some of my thoughts on Unum's technology and the potential upside of Seattle Genetics in leveraging it.

Unum is introducing Fc receptors (CD16) into T cells, which otherwise normally don't express these molecules. This allows T cells to bind to antibodies, and those antibodies to trigger T cell activation through 4-1BB and CD3-zeta signaling. The idea builds off of CAR T cell concepts, but adds a twist that the antigen targets could be changed in vivo in the patient, something no other technology offers currently.

Unum technology analysis:

1. This might not be obvious to investors, but why T cells versus NK cells for therapy, which are also cytotoxic but already express CD16 and interact with Fc receptors. The answer lies in manufacturing ease and to a certain extent potency of T cells versus NK cells. T cells currently can be readily expanded from a patient with anti-CD3 and anti-CD28 antibody coated beads to a scale ready for a patient in a 1-3 weeks. The best NK cell expansion protocols rely on K562 cells expressing 41BB ligand as stimulants for expansion and take longer. Using a second cell line, K562 adds cost and complexity to the manufacturing process. The Campana lab, where Unum's technology originated, is actually an expert on NK cells, meaning that if they thought they should leverage T cells, it should tell you something about current NK cell limitations.
From Unum Therapeutics website

2. One of the central advantages of Unum is the ability to re-boost modified T cells with anti-cancer antibodies once the T cells are already in the patient. However, I have concerns about the idea that one could administer new anti-cancer antibodies into the patient to re-arm the T cells at the tumor site. One obstacle is the anti-tumor antibodies reaching deep into the solid tumor, which we already know is difficult. In this regard, CAR T cells with scFv domain on board are possibly better in being able to migrate through dense extracellular barriers. Unum might be channeling the lower hanging fruit of hematopoietic cancers first, and indeed their first targets are CLL and NHL via CD20 antibody.

Assuming this re-arming is possible, the second obstacle is if pulsatile activation of T cells with antibodies will lead to their persistence in vivo. There are many facets to consider with this strategy. The positive spin would be that it is the continuous activation of CAR T cells now that lead to their exhaustion, such that a pulsatile activation would lead to continued persistence and Unum has a genius breakthrough on hand. The negative spin would be that T cells need a more chronic antigen stimulation to persist, and that lack of activation would lead to their cell death. The persistence parameter will be crucial for any future clinical trial, and might require perhaps similar selection for central memory T cell phenotypes pre-infusion in order to optimize the process.

3. I posted this article on Twitter before, but in general, CARs are the most sensitive molecule for detecting antigen on the surface of tumor cells. This has led to their great efficacy, but perhaps also to cytotoxic effects (on target, off tissue). By comparison, bispecific antibodies engaging CD3 need higher antigen thresholds on tumors in order to activate T cell cytotoxicity when tested against the same target antigen head to head.

The Unum play can be seen as a hybrid of CAR and BiTE approaches. Cross-linking CD3 on T cell surface has certain geometric constraints limiting efficacy, which the Unum strategy lacks since they mimic natural CD16 binding on T cell surface. Furthermore, Unum can tailor make a T cell receptor to recognize antibodies via CD16, but in contrast to CD16, transduce a more maximal signal (with 4-1BB costimulation) than most bispecific approaches can through CD3 epsilon engagement alone. Antibodies should be more flexible than their BiTE counterparts and can engage two different antigens leading to higher affinity binding. Thus, Unum might have significant advantages over Amgen's BiTEs for example, but with the big caveat of needing an additional cell therapy product to leverage this benefit.

The Campana paper that founded Unum suggested an approach where one transfects mRNA for the receptor inside T cells, and then infuses T cells into the patient. Antibodies would then be infused into the patient, allowing for any number of antibodies to do the trick. Incubation with antibody before infusion is possible, but the duration of efficacy should be limited since receptors will be turned over and the accompanying antibodies degraded fairly quickly. By comparison, a similar approach of transfecting mRNA into T cells will produce new CAR molecules continuously for 2-3 days. Of course, with the mRNA approach, the downside is optimizing different scFv CAR variants, whereas antibodies won't have this limitation. One could also mix and match various antibodies for the initial infusion, which is an advantage of Unum's approach. Note that Unum's cells, if potent, might degrade the antibodies more quickly than current pharmacokinetics studies with antibodies, something that should be monitored in trials.

Unum could be seen as competition for mRNA CAR players, but their later programs are all using stable viral vector expression, indicating they intended to try repeated antibody dosing to provoke CD16 - T cells inside the body.

4. I think an underrated concern about Unum's strategy is the effects of host antibodies on the T cells administered. Unum relies on a dance of two specific things finding each other at the tumor site to pair for destruction. One can imagine that additional layers could be added to this parlay to make it even more specific. The problem is that the events might just be so rare as to be inefficient.

This inefficiency could be driven by host antibodies outcompeting Rituxumab, for example, for the CD16 receptors on the outside of T cells. Unum can create high affinity CD16 receptors, but these should react to all antibodies, including endogenous ones. Upon infusion, their cells might rapidly be saturated with these decoy antibodies. In the Campana lab paper, they used an immunodeficient mouse model, which does not make any host antibodies, such that the question of competing antibodies remains.

I'm not sure if Unum is pursuing this, but this inefficiency could paradoxically turn into an advantage in other settings. For example, if the body is beginning to fight an infection, it has produced some antiviral IgG's for instance. Perhaps infusing Unum's modified T cells into the patient would allow increased potency of those hose antibodies for their effects.

The unknown dangerous side of this is to what extent people today have auto-reactive host antibodies circulating in us. It could be possible that a large bolous of Unum's T cells could enhance the activity of these molecules, and thereby lead to dangerous effects. There is some unexplored risk there in transfusing essentially un-naturally enhanced Fc-dependent effector cells. Patients out there do have the V158 mutation in CD16, but linking that to 41BB-Zeta signaling is completely novel addition and could create toxicity.

Summary: The best spin for Unum versus Juno and Kite would be if antibodies do readily penetrate the tumor, and the T cells persist and localize to the tumor well, in which case, the technology for doctors to change on the fly which antigen is being targeted would be very powerful, particularly when escape mutants are expected.

Seattle Genetics side:

From Seattle Genetics perspective, it's certainly a low risk and high reward move. They are already developing anti-tumor antibodies. They can give Unum a unique portfolio of new targets for their cell therapy. One question is if Seattle Genetics will eventually modify their antibodies to tailor them for Unum's purposes, instead of a principal purpose for their antibody drug conjugate programs. I would keep an eye on this going forward, since it would indicate an investment of their R&D resources and production facilities toward really pushing cell therapy forward and signal a departure from previous strategies.


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