Investigating Immunogenicity In Sub-Q Delivery With The Subcutaneous Consortium

In this episode of In Combination, representatives from the Immunogenicity subteam within industry association The Subcutaneous Drug Development & Delivery Consortium join host Tom von Gunden to discuss the role and impact of immunogenicity in biotherapeutics product development for sub-Q delivery. Members of the subteam describe the group’s focuses on degrees of desired or acceptable immunogenic response, as well as on industry harmonization of assays employed in preclinical and clinical modeling. 

Episode Transcript

Tom von Gunden, Chief Editor, Drug Delivery Leader:

Welcome to another episode of In Combination. My name is Tom von Gunden, Chief Editor at Drug Delivery Leader and your host for the series.

Today, I am pleased to be joined by members of the Immunogenicity subteam within the Subcutaneous Consortium. [Full name of the organization: Subcutaneous Drug Development & Delivery Consortium]

We did an episode introducing the consortium to our audience a few months ago. [See Going Deep On Delivery With The Subcutaneous Consortium.] And so today, I'm picking up for an update with the Immunogenicity team.

So, folks from the team, could you please introduce yourselves and let us know where your day job is, what your title and role is there, and then, briefly, how you became involved in the Subcutaneous Consortium and, specifically, the immunogenicity subteam?

Nicole Buist, Board Member & Immunogenicity Subteam Co-Lead, SC Consortium:

Sure. Thanks, Tom. Thanks so much for having us today to talk about the Immunogenicity subteam. We're excited to be here.

My name is Nicole Buist. I've been at Merck for 19 years. I'm currently leading a biologics drug product development and biopharmaceutics team within sterile product development at Merck.

I've been involved with the Subcutaneous Consortium since 2020, and I've been the subteam co-lead since 2022.

 Great. Well, it's my pleasure to have you here. Thanks for joining.

Jochem Gokemeijer, Immunogenicity Subteam Member, SC Consortium:

My name is Jochem Gokemeijer. I am at Johnson & Johnson. I am a Distinguished Scientist there at the Biotherapeutics Discovery organization. I've been there about two years, and before that, I've been at several other pharma companies.

I really joined the Subcutaneous Consortium pretty much right away after I joined Johnson & Johnson. So, for the last two years.

 Great. Thanks for joining.

Manjunatha Shivaraju, Contributing Partner, SC Consortium:

My name is Manjunatha Shivaraju. I'm a Principal Scientist at Boehringer Ingelheim, where I work in materials and analytical sciences, supporting the CMC development of small molecule biologics and advanced drug delivery systems. I've been at Boehringer Ingelheim for five years.

I have been actively involved in the Subcutaneous Consortium since 2023, representing Boehringer Ingelheim as a contributing partner.

Great. And, again, my pleasure to have you here. Thanks for joining.

So, Jochem, I’m going to turn to you in a second to start us off on this one.

Hopefully, our audience knows at least as much as I do, which is that immunogenicity refers to the ability of a substance to induce an immune response in the body. And there are [responses] that we want to have happen. And that would be, for example, in the case of vaccines. And then there are ones that it's not desirable to have happen: for example, in the case of delivering biologics-based therapies.

So, Jochem, could you tell us — maybe it's obvious, maybe it's not: How does immunogenicity fit within what anyone would think about when they're thinking about subcutaneous drug and biologics delivery?

Gokemeijer: Yes, absolutely. So, I think you put it very well. Immunogenicity is really an unwanted immune response towards a biotherapeutic, the opposite of the wanted immune response to a vaccine. And so, why do we think that is, or what's our understanding for why that could be a problem?

An immune response to a biotherapeutic is characterized, in most cases, by anti-drug antibodies [ADAs]. And that's the immune response that a patient would mount against a biotherapeutic.

Now, the challenge with anti-drug antibodies can be varied. And it can vary, really, from very serious safety concerns, as in anaphylactic shock. Or, you get an immune complex causing deposits in your kidneys, like a serum disease. Although, I will say, serious safety events are fairly rare.

What we see much more often is that the anti-drug antibodies influence the function of the drug. And it can either be antibodies binding to your drug and [changing] how the drug behaves in the system. Or it impacts the exposure, meaning you can either get an accelerated clearance off your drug, meaning your drug disappears from the system much faster than expected and, therefore, you would have less efficacy.

Or the opposite could happen: a drug would stay in the system much longer than expected or modeled. And then you run the risk that you get exaggerated toxicology findings.

Besides that, we also run the problem that, if an anti-drug antibody interacts with your drug, particularly at the positions and regions that are critical for function, you would neutralize the function of the drug. And then you would lose function of the drug; you would lose efficacy. And then you really don't have any efficacy of your drug anymore, which is obviously not good for the patients.

So, when it comes to subcutaneous, it's not that different, as in we still would introduce the drug to the system. But we do know that a lot of our organizations like to move to a subcutaneous dosing of a drug just because it's much more convenient for the patients. You can do it at home. So, for a lot of organizations, we drive towards enabling subcutaneous dosing.

Now, we have pretty good evidence, and we have seen that subcutaneous doses might have a different immunogenicity profile, in most cases. Then, we see an increased number of patients that mount anti-drug antibodies. And so, that is a challenge for us, and we would like to better understand that. And that's really one of the objectives of this consortium: to understand what is different in that scenario. And can we develop knowledge and models and tools to anticipate and predict that.

Great, great. Well, thank you for the foundational context-setting and laying out the landscape there.

Again, perhaps it's a bit obvious, but, Nicole, if you could highlight the key reasons why, among the work of the Subcutaneous Consortium and the laying out of the initial landscape of subteams to focus on particular areas: How and why did immunogenicity rise to the top as one of those key areas for some members of the group to focus on?

Buist: Yes, that's a really good question, Tom. So, there is a bit of discord in the industry on the topic. And that really stemmed from some earlier reports that were published where researchers would take an IV-administered biotherapeutic and dose it sub-Q. And there would be a clinical report of increased immunogenicity from that change in administration pathway. And that's real, and that's true.

But the way that those publications came and their timing created this concept in the industry that every time you dose an IV therapeutic sub-Q, you're going to have an increase in immunogenicity. And for all the concerns that Jochem just went through, that’s bad.

But time has passed since those initial reports, and the industry has really exploded in biologics sterile product development. So, we've learned a lot more. And what you're seeing now are more and more reports where you can have the same immunogenic response from IV to sub-Q for a given biotherapeutic. Or sometimes you can even see a decrease in immunogenicity when dosed subcutaneously in some cases.

And so, if you think about that, even if — also what we're seeing is — even if it's higher [in sub-Q] than IV, it doesn't always have those bad effects that Jochem was talking about. Sometimes they just don't matter. And so, what we like to do, in general, is try to reach an accepted position in the industry of how we view immunogenicity, and whether or not we think it's a concern as we develop our products.

Gotcha. Yes, so, it sounds like what you're describing is some attempt to address what some might call misconceptions or misunderstandings or concerns about what we mean. So, thank you for letting us know that. That explains the general rationale for the focus.

But there must be some specific problems within that area that you folks have decided really need to be addressed head-on. Can you give us a view into the sorts of problems that are being addressed?

Buist: Sure. So, there are two main ones.

If we think about the assays that we use: As anyone is doing any drug product development — sterile, oral, vaccines, anything — we're always looking for in silico, in vitro, in vivo, preclinical models to inform us ahead of very expensive clinical trials that we really need to go right the first time we're running them.

And so, if you look at that in the immunogenetic space, those models are not necessarily predictive of what we're able to see in the clinic. Sometimes they are — and there's some great manuscripts out there where we are seeing that correlation — and sometimes they don't seem to correlate.

So, this group is looking at all those assays as a whole to sort of kick the tires and see what are the best assays that we should be using.

And then further, if we think about a harmonized view on the topic and a harmonized view on the assay:  I'll draw a parallel there to oral product development, where, if I mentioned the BCS classification system [Biopharmaceutical Classification System] and said, ‘This molecule is a BCS Class 1.’  You're doing oral product development, then you likely have a sense about that molecule just from hearing that phrase. You know it's high solubility; it's high permeability. An oral tablet should be no problem to develop.

We don't have that same harmonization in the immunogenetic assays that we're running. And so, something that we're working towards as a group is to find the right model that we can agree upon across academic and industrial partners of what's the agreed-upon model that we're going to baseline the industry on so that we can compare our products across the industry and learn more as we continue to develop these products.

 Gotcha. Yep. Thanks, Nicole.

Well, obviously, given the work that you just described, there must be people doing the work.

So, Manju, I'm going to ask you to tell us about how the subteam organizes itself and approaches its work and executes on it.

Shivaraju: Yes, sure, that's a great question.

So, we work in a unique way. The uniqueness is the combination of expertise, collaboration, and scientific reach that we bring in together.

Firstly, our group is highly multidisciplinary, and we bring together experts from formulation development, analytical sciences, bioassays, protein engineering, drug product development, and translational sciences as well.

What makes this particularly powerful is these experts are not operating independently. Instead, they collaborate closely and challenge each other's thinking. For example, a formulation scientist who understands how excipients and manufacturing processes or delivery characteristics may influence immune responses can sit side-by-side with an immunologist who specializes in predictive immunogenicity assays.

This conversation often generates new perspective that would not emerge within a single discipline alone. This cross-functional approach allows us to identify potential risks earlier, ask better scientific questions, and develop robust mitigating strategies throughout the development life cycle.

A second aspect that makes our team unique is our culture, common goal, and willingness to share. Everyone in this group shares common goals, helping develop safe and effective therapies while minimizing immunogenicity risk for patients.

Because of this shared purpose, there is a strong spirit of openness and collaboration. Team members openly share experiences, lessons learned, unsuccessful approaches, and emerging insights. We recognize the fact that advancing science often involves learning from challenges and failures, not just successes.

This willingness to share knowledge accelerates learning for everyone involved and helps break down the organizational silos that can sometimes exist across the companies and disciplines.

The third characteristic that differentiates our group is our strong networking. Over the years, consortium members have established meaningful relationships with leading academic researchers, industry experts, regulatory scientists, and key opinion leaders in immunogenicity. These connections allow us to stay informed about emerging technologies, novel assay platforms, evolving scientific concepts, and changing regulatory expectations.

Importantly, we do not simply follow the literature; we actively engage with the experts who are helping shape the future of the field. Through this interaction, we gain visibility into new scientific developments and can bring best practices and innovative thinking back into our projects and consortium activities.

Finally, what makes us unique within the consortium is our commitment to collective problem solving. Immunogenicity is a complex challenge that affects the entire biopharmaceutical industry. No single organization has all the answers. By bringing diverse perspectives together and openly sharing knowledge, we can address common challenges more effectively and advance sciences for everyone.

This collective spirit is really at the heart of what makes our working group a special one.

Gotcha. Well, I'm going to take the wild leap in faith that, when you have a multidisciplinary group of experts who are willing to be open and collaborative, they must get things done. It sounds like it has to be effective in some way. So, I'm just going to take a wild guess that there have been significant achievements.

Feel free to highlight. And, Manju, since your voice has warmed up, if you want to do that, that would be tremendous.

Shivaraju: Our first major milestone, our achievement, was a successful workshop we organized in 2023. It was a highly interactive, in-person event that brought together a broad range of experts, including members of the SC Consortium, external pharmaceutical industry leaders, academic researchers, and subject matter experts in Immunogenicity.

The diversity of expertise and perspective created rich, candid discussions that are often difficult to achieve in traditional conference settings. During the workshop, we explored several important topics, including current challenges and opportunities in predicting immunogenicity risk for subcutaneous biotherapeutics. Advances in analytical, bioanalytical, and immunological assessment methods used to evaluate immune responses.

Thirdly, the emerging in vitro translational approach for improving the predictability of immunogenicity assessments. Lastly, the strategies for bridging preclinical findings with clinical outcomes, as well as evolving regulatory expectations and best practices for immunogenicity risk management.

These discussions highlighted both progress that has been made and the areas where additional scientific innovation and collaborations are needed. Importantly, the impact of the workshop extended well beyond the event itself. We carefully captured the key discussions, insights, and recommendations generated during the meeting, and worked collaboratively to synthesize them into a comprehensive manuscript.

I am pleased to share that this manuscript has been submitted to a peer-reviewed journal. We are hoping to get it published soon. Our goal is for this publication to serve as a valuable resource,  not only for scientists but also regulators, by providing a consolidated view of current challenges, emerging approaches, and future opportunities in immunogenicity assessment.

Beyond the workshop and manuscript, I believe one of the greatest accomplishments has been strengthening collaboration across organizations and disciplines. We have helped build a network of experts who are committed to sharing knowledge, addressing common challenges, and advancing the science together.

Great. Well, given that kind of work that's been done, I am assuming that there are still things in motion and next steps and exciting things to happen.

So, Nicole, I'm going to ask you to start off by telling us what's currently in motion and what's next up.

Buist: Sure. Yes, as Manju just noted, we hope to have the discussions and the conclusions and the relevant case studies from our workshop published shortly. And then from that publication, we are working on distilling all those learnings into a webinar that will be maybe a slightly easier-to-digest format for certain folks.

So, that really supports our mission about sharing the messaging and getting cross-company harmonization of how we're viewing the topic. And we're really excited about it because many of the key authors who authored that publication are going to be the key speakers for that webinar.

And we're going to design it so that, in that initial recording, we'll have a question-and-answer period where people can actually interact with those experts. And I'm excited to see what sort of questions come out from people who are also interested in immunogenicity, but not necessarily on our subteam — to hear those different perspectives.

We're also really excited, as Manju mentioned, to continue pushing the boundary and expanding what we understand in this space. And so, through the SC Consortium, we have achieved some funding. And we're going to fund some research between our subteam and Professor Balu [Sathy Balu-Iyer] at University of Buffalo at SUNY.

And that work should be an opportunity to look at a series of molecules that are known in the industry, with known clinical data, in a harmonized lab setting where they are all run in the same assay, with the same experts. And then we will bring both the industrial and academic perspectives together to analyze that data set. So, we hope also to be able to share that with the community, pending the success of those experiments.

And then if we are able to continue to validate the models that are in Professor Balu's group, we also want to take the next step with really understanding more about the critical quality attributes of our products, meaning, a lot of these products, as they transition from IV to sub-Q, are combination product development. So, they are prefilled syringes, autoinjectors, on-body infusers, for example.

And there can be some attributes of those container closure systems. For example, silicon oil, or leachables, or things that look different from a sterile liquid in a vial. Are we able to take some of those variables and test them in the model and see if they have an impact on immunogenicity or not?

Similarly, you can think about all of the handling issues that could come up. So, if you think about sterile product processing, you're thawing a drug substance, you're filtering, filling it into vials. It gets packaged, gets shipped all around the world, either to clinical trials or all the way, if it's commercialized, to the patient's hands. All along the way, there could be agitation and plane transfers or barge transfers, for example. We want a chance, from a CMC perspective, to see: Does that manipulation of the product have an impact on immunogenicity, and can we answer some of those questions as well?

So, we are really excited to take the work that we're doing to the next level and really push the boundary of what we understand in the space. And then to do that in a collaborative nature with our academic partners is something we're very excited about.

The last thing that we're working on is a cross-industry survey, and Jochem has been leading that effort with my [subteam] co-lead, Sophie Tourdot, who couldn't be here today. So, I'll turn it over to him so he can tell you more about that survey.

Great.

Gokemeijer: Thanks, Nicole. Yes, as Nicole mentioned, we do have a set of tools available to us — in silico, in vitro, and in vivo assays — that we are using and that we are constantly developing. Particularly from the aspect of how this would apply to immunogenicity related to sub-Q dosing, we know that people are thinking about developing new assays to look at this. And that's a quickly evolving field.

So, what we would like to do is get an idea of how people are using these assays. And are they doing things differently? Are they developing new assays, particularly for sub-Q dosing?

Now, since we are using these tools and assays more often and we'd like to use those tools to submit to the regulatory authorities, there's also a need for us, but also from the authorities, to have a more harmonized approach. How are these assays run? And what does the data actually mean that comes out of it? How reliable and how reproducible is that? That's the push also from the health authorities.

We really feel that, if we get a nice landscaping of where everybody is [who are] doing these kinds of assays, it will give us an opportunity to identify where the gaps are, what are people working on. It gives the people within their organizations trying to make resources available to do these kinds of assays some support [regarding] this is where the industry is going.

But it also, for us as a consortium, gives us the opportunity to identify: What are those tools? What are those critical parameters that we might want to work on for further harmonization?

Gotcha. Well, thank you for that, Jochem. It may have seemed that your explanation should serve as a final, excellent word for the audience today.

But I'm actually going to ask you to feed one last line in here. And that is, if folks in our audience are interested in the work of the Subcutaneous Consortium, and specifically the Immunogenicity subteam — either for updates and/or to potentially contribute or participate — how do they do that?

Gokemeijer: Well, thank you so much, Tom. Yes, excellent. If people are interested in joining the Subcutaneous Consortium, particularly the Immunogenicity subteam, go to the website for the consortium. You can find us there, sign up, and join.

Excellent.

Well, Nicole and Manju and Jochem, I want to thank you for joining me to share updates with our audience at Drug Delivery Leader about the work of the subteam and the consortium. And to that audience, I want to thank you for joining again for another episode of In Combination. And we'll see you next time.

The Episode’s Featured Guests

	Nicole Buist Board Member and Immunogenicity Subteam Co-Lead Subcutaneous Drug Development & Delivery Consortium Executive Director, Sterile Product Development Merck
	Jochem Gokemeijer Immunogenicity Subteam Member Subcutaneous Drug Development & Delivery Consortium Distinguished Scientist, Biologics Discovery Johnson & Johnson
	Manjunatha Shivaraju Contributing Partner Subcutaneous Drug Development & Delivery Consortium Principal Scientist Boehringer Ingelheim