Recombinant Antibodies: Advantages to the IVD & Therapeutic Markets


Hello and welcome to our second video of our Carl Chat series. In the first video, our chief scientific officer, Dr. Carl Ascoli and our product manager, Todd Giardiello, discuss COVID-19 and the effects it had on the biotech industry. Today, they'll be discussing recombinant antibodies, what they are, how they're produced, and the advantages they provide to the IVD and therapeutic markets. We hope you enjoy the discussion. Let's begin.

Todd Giardiello: Thank you, everyone, again for joining us with another Carl Chats. With me is Dr. Carl Ascoli and today we will be talking about recombinant antibodies. So, Carl, as a kickstart. What are recombinant antibodies?

Dr. Carl Ascoli: Good morning, Todd. Well, very simply, recombinant antibodies are monoclonal antibodies with a defined genetic sequence. So, not only is the nucleic acid sequence of the antibody known, the amino acid sequence of the antibody is also known. And it can potentially be produced without generating an immune response in a host animal, potentially.

Todd Giardiello: It's interesting, so then how are recombinant antibodies produced?

Dr. Carl Ascoli: Well, there's no one way to produce a recombinant antibody. In fact, there's many ways. One of the most common ways is to clone the nucleic acid from, for instance, the B cells of a hyper-immunized animal or from a hybridoma cell line that's been produced and subcloned. And in both of those instances, actually, the recombinant antibody is originating from an animal source. Typically, what happens when you make a recombinant antibody is after you clone it, you put it into an expression library for selection and subcloning. In some instances, you can make a recombinant antibody that is animal-free. For instance, you can directly synthesize a nucleic acid and then express the protein that makes the recombinant antibody.

Todd Giardiello: So then how does the manufacturing process of recombinant antibodies differ from something that we would expect to be a more traditional monoclonal antibody?

Dr. Carl Ascoli: Well, in general terms, making a recombinant antibody is more difficult because there are more steps involved. And therefore, the cost of generating a recombinant antibody is higher compared to a conventional hybridoma-based monoclonal or a polyclonal antibody. But if the antibody that you're producing is needed in large quantities, if there's lots of demand for that material, and if, in fact, you're going to use it over a long period of time and generate multiple lots, then the cost and difficulties in producing the recombinant are outweighed by eliminating the costs of remanufacturing and the difficulties that go along with remanufacturing.

Todd Giardiello: So how do recombinant antibodies compare to the traditional murine-derived monoclonal antibodies?

Dr. Carl Ascoli: Sure, well, conventional hybridoma-based monoclonals are produced by well-defined steps. You hyper-immunize an animal, you fuse the splenocytes with the hybridoma with a myeloma cell line to make the hybridoma. And then you go through subsequent rounds of subcloning and screening until you get a truly monoclonal cell line. As for many cells, hybridoma cells are subject to cell death, chromosomal rearrangement, and clonal drift. So even though you make the hybridoma cell line, things could change over time. And conventional hybridoma-based monoclonals don't have a defined genetic sequence. And that is an issue in many areas as it relates to therapeutics and reproducibility.

Todd Giardiello: So how does that differ from monoclonal antibodies?

Dr. Carl Ascoli: Well, a recombinant antibody can be produced again with a known genetic sequence, that's one of the big differences. And therefore, it can be produced and potentially reproduced in an animal-free environment. With the known genetic information, you can use conventional molecular biology techniques to produce the proteins with the same sensitivity, specificity, and reproducibility every time you produce the antibody.

Todd Giardiello: So what are some of the key benefits to using recombinant antibodies?

Dr. Carl Ascoli: Sure. Well, again, in my opinion, recombinant antibodies are very well suited for long-term use, where multiple lots are going to be required to minimize any performance differences over a long period of time. I think recombinant antibodies are best suited for the diagnostic and the therapeutic uses. In fact, most therapeutic antibodies today, if not all, are, in fact, recombinant antibodies. And one of the most significant benefits of recombinant antibodies is that the sequence itself can be engineered. So you can modulate the properties, you can optimize the properties of the antibody with regard to performance and stability, depending on what immunoassay you're configuring.

Todd Giardiello: So you had mentioned that there are some advantages, particularly to the diagnostic and therapeutic industries. Can you expand on that a little bit more?

Dr. Carl Ascoli: Well, sure. When an antibody is used for diagnostic purposes, typically it's needed in a large quantity. And it may have requirements of being needed over a long period of time. And you may need multiple lots. And in all of these conditions, you really have to have an antibody that is invariant from one lot to another and from one year to the next. So recombinant antibodies are really well suited here. In therapeutics, the argument is even stronger for using recombinants because of the fact that you have a known genetic sequence. And regulatory agencies, again, consider recombinant antibodies as drugs, and you really have to define the basic composition of a drug. So that's a very strong point for using recombinant for therapeutics.

And also, as I mentioned before, the ability to engineer the sequence gives you a strong advantage. You can modulate the sensitivity, the specificity, and even the stability of a drug. For instance, you can deploy a therapeutic that might be cold chain independent in a particular use.

Todd Giardiello: So we've been talking a lot about the benefits of recombinant antibodies, but are there any limitations to their production and performance?

Dr. Carl Ascoli: Yeah, there are technical limitations. And I did mention earlier that initially there could be some cost considerations as well. But for instance, technically, if you are producing a recombinant antibody that has a heavy and light chain, like a conventional antibody, there may be large libraries that need to be constructed in order to obtain an antibody with the properties that you want. On a cost basis, if you're doing research, for instance, some antibody targets and antibodies themselves may be better suited to first producing a conventional polyclonal antibody, which is very cost-effective to produce. And once you, in fact, determine that there is biological significance to the target when you're doing research and that that antibody is going to be used by a lot of people, then there may be the justification to make a recombinant antibody. But I happen to be one of many people that think that polyclonal antibodies are very valuable tools as well.

Todd Giardiello: Are recombinant antibodies better suited for any immunoassay applications, more so than, say, polyclonal or monoclonal antibodies?

Dr. Carl Ascoli: My answer to that would be generally no. However, if the recombinant antibody is a single domain antibody, where there is only one binding event, then any immunoassay that requires bivalent antibodies for binding may not work well compared to an antibody configured with a heavy and light chain. Again, I'm of the opinion that recombinant antibodies work best for diagnostics and therapeutics, and I think they show less of a bias one way or the other, depending on the immunoassay that they're going to be used in.

Todd Giardiello: So let's conclude with some market trends. The recombinant antibody market is expected to increase by about seven percent for the next few years, while the total antibody market is expected to increase about 11 percent during that same time. Do you expect the differences in these trends to continue or will the benefits that we've talked about today of recombinant antibodies sway amino immunoassay manufacturers in their direction?

Dr. Carl Ascoli: Sure. I guess my answer would be yes. I think recombinant antibodies will continue to gain market share. There are trends specifically in Europe right now to embrace an animal-free approach to antibody production. And that may actually accelerate the rate of growth of recombinant antibodies in the marketplace. But remember, many of the strategies for producing recombinant antibodies actually start with libraries created from hyper-immunized animals. So the perceived gain from an ethical perspective may not be as advertised because ultimately a lot of these recombinants do derive from animals.

Todd Giardiello: All right, so there's a lot of interesting information in there. I'd like to thank Dr. Carl Ascoli again for joining us today, and we hope to see you all again later with another Carl's chats. Thank you, Carl.

Dr. Carl Ascoli: Thank you, Todd. It was enjoyable, talk to you next time.

Todd Giardiello: Thank you.