Lenti- vs Retro-, and Increasing Capacity for Multi-Vector Development

Georgi Makin
Bill Vincent
8 August 2022
Cell Therapy
Viral/Non-Viral Vectors
In this interview, we explore the vector landscape with Bill Vincent, Founder & Executive Chairman at Genezen, considering everything under the lenti- and retrovirus umbrellas, as well what the impact of increased capacity for multi-vector development and manufacture could be for the acceleration of advanced therapies to market.

1 – First of all, could you tell me a little more about yourself and your role at Genezen?

I am the founder, original CEO (for 7 years) and now Executive Chairman of Genezen. My educational background is in microbiology and biochemistry with an MBA concentration in accounting. I spent 13 years in the consumer products sector working in quality assurance, manufacturing, marketing, finance and business planning. The last 22 years have been spent working with various start-ups, first in the medical device space, and then in cell and gene therapy for the last 12 years.

2 – For this feature, we are comparing different vectors used in the manufacture of advanced therapies. If we consider lenti- first, what are some of the top challenges associated with development and manufacturing with lentiviral vectors?

Lentiviral vectors are great in that they can carry such a large transgenic, and do not have a tendency to insert near an oncogene. The challenge is in the manufacturing. In an ideal world of vector manufacturing, you would develop a producer cell line that incorporates all of the plasmids needed to make your vector with a high titer. Unfortunately, with lenti-vectors, the VSVG envelope – that is widely used – is toxic to the host cell. Some have tried using a tetracycline control on the envelope plasmid, which will work to control the envelope. However, you must get all of the tetracycline out before starting production, otherwise the tetracycline will dramatically reduce your titer. This, along with other issues, have made it difficult to be able to make producer cell lines for lenti-vectors. The effort continues with varying degrees of success. Traditionally, lenti-vectors have been made using transient transferring of the plasmids into adherent 293T cells grown in 10-stack cell factories. This process is material, space and labor intensive, and does not scale very well.

Want to find out more? There’s more information on lentiviral vector challenges in this White Paper >>

3 – How is Genezen working to overcome these challenges?

The Genezen process development team has worked with several clients to transition them out of the cell factory platform and into various fixed bed media bioreactors, which provide a more scalable platform. The team has also adapted the 293T cell line to grow in suspension with serum-free media. This allows for a saleable system that can go from wave bioreactor bags up to stir tank bioreactors.

There’s more information on overcoming challenges associated with lentiviral vectors in this White Paper >>

4 – How do these challenges compare to retroviral vectors?

From a manufacturing perspective, the Gamma Retroviral Vectors (GRV) have a clear advantage in that you can develop a producer cell line. This means you can eliminate the transient transaction step and the plasmids and other materials required for this step. By using a producer cell line that is developed from a single clone, you have consistency in vector production from batch to batch. These can also be grown in a fixed media bed bioreactor. This gives you a way to scale the production. While I haven’t personally seen these producer cell lines used in a stir tank bioreactor, I tend to think that they could probably be adapted to work.

Discover more about the challenges associated with retroviral vectors with this White Paper >>

5 – How is Genezen working to mitigate these obstacles?

Our development team is continually looking at new technology and platforms that can help us to overcome some of the current technical limitations. We have collaborated with companies working to develop producer cell lines for lenti-vectors. We are also working with equipment manufactures to adapt their system to lenti- and retro- vectors. We recognize the high cost of manufacturing and are always looking for ways to improve yield, and increase scale.

This is explored further in this White Paper >>

6 – Genezen recently opened a new facility for multi-vector development and manufacturing. Could you speak to how increased capacity for this area of development might impact the speed to market for advanced therapies?

For years, the bottleneck has been in getting vectors made for Phase I and II clinical trials. Before Covid hit, the backlog for scheduling a production run was close to 24 months at most viral vector CDMOs. Since then, we have seen additional capacity come online, and it seems like the pace of new companies jumping into the space has slowed a little. That said, the available capacity is still very tight and is compounded by supply chain challenges.

My advice to anyone trying to get a viral vector product into a clinical trial, is to start early working with your CDMO. That also means putting down deposits to lock in your GMP runs. Depending on the CDMO, you will get different degrees of freedom as to your ability to move the run dates. At Genezen, we are customer focused and believe that we not only provide a service for our clients but we must also be of service to our customer. Not all CDMOs understand that distinction.

How are you enjoying this interview? Let us know your thoughts, here >>

7 – What might be your advice to anyone getting into this space and working to commercialize advanced therapies?

Everything takes longer and costs more than you think it will. There will be hurdles and setbacks along the way, so plan ahead and think of the possible risks to your plan and devise ways to mitigate them. Build a great team to work with you and a strong network to advise you and to call on when you run into those hurdles. That includes finding a CDMO who shares your vision, is excited about your project and wants to truly be a partner working with you hand in hand. If your CDMO isn’t offering suggestions and proposing innovative ideas, then you are just another client and they are not your partner.

8 – Looking ahead, what should we be looking out for from Genezen in the near future?

We are always trying to stay one step ahead of our clients and anticipating their needs, and so we are working with equipment suppliers to develop new platforms for lenti- and retro- vectors. It was mentioned earlier that we had opened a new facility with process development labs and GMP production suites. We have already started the next phase of expansion which will triple our lab space and double our GMP production space. We are also looking at other opportunities and ways to serve our clients. So stay tuned!

9 – Do you have any final thoughts you would like to share?

Developing these therapies is hard. You have to remember that if you save just one life then it is all worth it. I think most people in this industry got into it because, like me, they love the technology and hope they can help improve people’s lives. There is a quote that says; you are successful if you have made the world better for just one person. I forget who actually said it, but I aking the world a better place is a pretty good goal.

Enjoyed this interview? Learn more about Genezen with this podcast episode, featuring Genezen CEO, Ray Kaczmarek >>

This interview was produced in partnership with Genezen. The feature image used was provided by Genezen, with permission granted for use for the purpose of this interview. 

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