18 January, 2019
The U.S. Food and Drug Administration (FDA) has rejected sacituzumab govitecan also known as IMMU-132, a novel, investigational, antibody-drug conjugate or ADC consisting of SN-38, the active metabolite of ir...
Published on 27th March
EAG Laboratories is a global scientific services company providing testing, analytical and characterization services to clients across a vast array of technology- and life-science-related industries. The company has recently made significant investments to support its growing life science offering and customer base, including the recent expansion of its cGMP pharmaceutical laboratory in Columbia, Missouri.
This expansion is directly related to the biotech and pharmaceutical industry’s critical need for high-quality contract laboratory partners who understand the regulatory guidelines, can perform required risk assessments and have the capacity to execute validated analytical procedures. But it also gives the company’s experienced and dedicated team of highly skilled scientists a state-or-the-art environment to assist customers in successfully execute drug development projects.
To see how these developments impact the development of novel drugs, including ADCs, we sat down with Glenn Petrie, Ph.D., Senior Scientific Advisor at EAG Laboratories.
With over 20 years of experience in support of biotechnology projects, Petrie helps EAG Laboratories’ clients find answer to challenging development questions unique to large molecule development. He serves as the primary business development contact for the company’s biopharmaceutical development projects.
PH: In your experience, what are some of the unique challenges presented by the complex nature of antibody-drug conjugates?
GP: Understanding biopharmaceutical stability and demonstrating biological activity are some of the most critical and challenging aspects of the development of novel therapeutic agents. This is, however, becoming increasingly difficult as we move towards molecules with multiple mechanisms, such antibody-drug conjugates or ADCs. Antibody-drug conjugates combine the target specificity of a monoclonal antibody with the therapeutic activity of a highly potent cytotoxic anticancer agent utilizing a variety of (linker-) chemistries. This results in an extremely complex structure.
Our team of highly dedicated and experienced scientists collaborate with our clients, offering them their experience and expertise in developing and optimizing a variety of bioassay methods for product potency and stability.
PH: What are some of the special considerations when developing analytical methods for ADCs?
GP: When developing methods for the analysis of ADCs our scientists take into account the unique properties of a specific ADC, including the drug-antibody ratio or DAR and drug load distribution.
DAR and drug load distribution are critical product quality attributes. A hydrophobic interaction chromatography or HIC method has been developed to determine the drug load distribution and DAR for a variety of ADCs. This is important, because, in general terms, DAR and drug load distribution determine the drug quantity to which a patient is exposed. In addition, each of these various drug loaded forms may differ in their pharmacokinetic/pharmacodynamic (PK/PD) characteristics.
Another important aspect to consider is that the linker chemistry applied and the cytoxin included in a specific ADC will modify the chemistry of the monoclonal antibody. As a result of changes to the surface of the antibody protein, this modification may result in increased antibody aggregation and/or decreased binding and cytotoxicity decreasing the overall stability and efficacy of the antibody-drug conjugate. SEC, antigen binding and cytotoxicity reflect overall 3-dimensional structure and are therefore Critical Quality Attributes.
PH: In March you presented a talk during BioPharma Asia 2017 in Singapore* discussing “ADC Development: Keys to Rapid IND Submission and Approval.” During the presentation you discussed the unique analytical challenges presented by the complex structure of antibody drug conjugates (ADCs) and the myriad of analyses required in support of a successful Investigational New Drug application (IND). How do you support your clients with an IND submission?
GP: One of the most critical aspects of an IND submission is to address all the the unique issues involved; to be complete, correct, and submit the IND in a timely fashion. Incomplete or incorrect information can cause delays in submission and may even result in a rejection of the IND. We use our extensive experience and expertise to support in our clients in submitting successful INDs. And we do that in an accelerated time frame.
During my presentation in Singapore I also highlighted proven ways to maximize the probability of a successful IND, while minimizing the time and effort required. This included critical biopharmaceutical characterization parameters and critical quality attributes or CQAs, but I also discussed studies that may be frequently overlooked, such as compatibility and residual solvents/metals/
PH: What makes an IND-submission for an ADC complex?
GP: It’s good to keep in mind there is no specific regulatory guidance to industry for ADC development. In their process to regulate ADCs, the FDA follows existing guidelines for both small drugs and monoclonal antibodies. As such, this process is a collaborative effort across product quality FDA-offices, including the Office of Biotechnology Products (OBP) and the Office of Pharmaceutical Quality (OPQ). OBP and OPQ primarily focus on the manufacturing of the antibody component of the ADC and the control strategy for the antibody intermediate, as well as for the drug substance and drug product. In addition, the small molecule review group at the OPQ is primarily responsibility for review of the adequacy of the payload and linker, conjugation reaction and aspects of the control strategy.
PH: What is the foremost important aspect the FDA – and other regulators are looking at?
GP: The FDA’s primary concern is safety. This is especially important for ADCs. These novel drugs contain one of many different cytotoxic agents that are far more potent than standard anticancer agents. And as a result of their cytotoxicity, with IC50 in the picomolar range. Consequently, to ensure the drug product, it is critically important to determine the concentration of unconjugated drug. The level of free, unconjugated, drug is usually in the 1-10 ng/mL range, making it very difficult to detect. Typically Liquid Chromatography-Multiple Reaction Monitoring/Mass Spectroscopy or LC-MRM-MS has the necessary sensitivity and specificity and will suffice. But ocassionally you’ll have to push sensitivity even further to determine free or conjugated drug down to 1 ng/mL or less.
PH: As part of your work, what should companies note about working with regulatory agencies – whether this involves the FDA or EMEA?
GP: One of the key aspects is to ask questions. Don’t be afraid to ask for clarification if the advice given is not clear. It will help you submit the correct information and avoid unnecessary and expensive mistakes.
But it is also important to understand the difference in the requirements of the different agencies. The EMEA, for example, places an emphasis on cell bioassays as part of their equivalent of an IND; the FDA does not. Generally the European requirements are more rigorous early in the process, but that difference quickly disappears in the following phases of the process.
PH: In your experience, why are pharma and biotechnology companies eager to work with companies like EAG?
GP: We’re scientists, not only by training, but as part of our natural curiosity. When we talk with a client, we speak scientist to scientist – and that is a real benefit because the biotech and pharmaceutical industries have a critical need for high-quality scientific partners who truly understand analytical methods and regulatory guidelines and can execute complex study designs. Our team of highly skilled scientists has a proven track record for efficiently advancing complex programs through the regulatory process. They bring deep insight to the analysis and characterization of ADCs, monoclonal antibodies, bispecifics, biosimilars, fusion proteins, pegylated proteins and other biotherapeutics.
When we start working with a client early in the development process we truly become an extension of their team. We are not just performing our analysis. It’s not just “throwing a report over the fence… ” as one might say. We become true collaborators. As a result we sometimes know more about our client’s molecules than the client.
In the end, I think that the reason why our industry partners want to work with us is our unique experience and dedicated – collaborating approach. That is what our clients are looking for and what makes EAG unique in the industry.
PH: What does the future of ADCs hold?
GP: Today there are only two ADCs on the market. But I expect that this will change quickly. When speaking with our clients my understanding is that most of them have very aggressive timelines. One of our clients mentioned that they expect submitting 2 INDs per year – each year – for years to come.
PH: …. that is a really big push…
GP: Yes it is. But according to some analysts this is still a conservative estimate. Several months ago, during World ADC Summit in San Diego, California, expert opinion seemed to suggest that there will be 15 ADCs on the market by 2020.
PH: How does that impact your work?
GP: Some of our clients have voiced legitimate concern when discussing the available capacity. But in reality, I don’t think that they need to worry. Earlier this year we started to increase our staff of scientists. We expect to increase the number of scientists by 35 – 40% this year and triple our dedicated cell bioassay capability in Columbia, Missouri.
With the strong commitment of our senior management team we expect to be ahead of the curve.
PH: Looking back over the last decade – what are some of the major accomplishments that excite you about the development of ADCs?
GP: The diversity in the development and the differences in the various platforms is exciting. For example, there are now two well established platforms developed by Seattle Genetics and the other by Immunogen. There is also considerable invested in the development of new cytotoxic payloads, additional linker technologies, and site-specific attachment.
I’m also excited about the improvement in controlling DAR. All these developments may help us to improve the efficacy and decreases the side effects of novel ADCs.
Looking towards the future, I can see the potential for applications beyond oncology and hematology.
That really excites me.
Last Editorial Review: March 27, 2017
* BioPharma Asia 2017, March 21 – 23, 2017, Suntec Convention, Singapore, Singapore
Photo 1.0: Glenn Petrie, Ph.D., Senior Scientific Advisor at EAG Laboratories Courtesy: © 2017 EAG Laboratories Featured Image: Singapore skyline at the Marina during twilight. Courtesy: © 2017 Fotolia. Used with permission.
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