Download Notes from Round Table 35 January 27, 2016

Notes from Round Table 35
January 27, 2016
Topic:
Analytical Challenges Related to Antibody-drug Conjugates
Characterization and Specifications
Facilitator:
Oscar Salas-Solano, Seattle Genetics, Inc.
Scribe:
Brian DiPaolo, AbbVie, Inc.
Scope:
Antibody-drug conjugates (ADCs) are becoming increasingly important therapeutic agents. ADCs
are manufactured through the chemical linkage of a potent cytotoxic drug to a monoclonal
antibody (mAb). As a result, ADCs leverage the selectivity of monoclonal antibodies (mAb) for
targeted delivery of the cytotoxic drug while minimizing exposure to normal tissues. Generally,
the conjugation process generates more complex and heterogeneous ADC structures than the
corresponding parent mAb. ADC’s heterogeneity presents challenges to both the analysis of
product quality attributes and setting of specifications. This table will discuss strategies to advance
ADC characterization and facilitate the setting of specifications.
Notes:
BULLET POINTS FOR DISCUSSION:
1. The selection of appropriate analytical methods for a specific ADC depends on the
properties of the drug-linker and the conjugation site (inter-chain cysteines, lysines,
engineered cysteines, Fc glycans, etc.).
a. There is significant variability here, depending on the drug-linker and its properties.
2. What quality attributes are relevant for ADCs?
a. DAR (drug-antibody ratio), even for site-specific ADCs is an essential quality
attribute.
i. DAR profile = safety profile that was tested in clinic
ii. It was acknowledged that manufacturing ADCs with a consistent DAR
profile is essential
iii. It is important to monitor what level of unconjugated product (both free
monoclonal and free drug/payload) is found in the ADC. It was
acknowledged that some manufacturing processes will have further
purification steps to remove these impurities.
iv. Developing a robust stability program is vital for monitoring the long-term
quality of the ADC. For example, is degradation seen? Is there a risk that
the ADC could "fall apart" over time?
1. Is "over-conjugation" a possibility for an ADC? Would this have an
impact on the stability profile of the ADC?
2. It was acknowledged that ADCs are generally put through same
stability program as a naked antibody.
b. Aggregation, subvisible particles due to hydrophobicity
3. What novel methodologies can be applied to advance the physicochemical and biological
characterization of ADCs?
a. The concept of leveraging in-process controls as part of overall control strategy was
discussed.
b. Mass Spectrometry was discussed as a very important tool to characterize ADCs.
c. A general discussion topic was around handling very toxic material on general QC
equipment.
i. You may only have a few labs that could handle these materials.
ii. Dedicated labs are an option.
iii. Robust cleaning is necessary.
d. The topic of whether there are good analytical methods to detect product variants,
especially when these attributes could be hidden by the drug conjugation process.
e. Peptide mapping is helpful -- higher order structure -- to determine what happens
to antibody after conjugation.
f. You will likely need to develop analytical methodology to detect degradation
products.
Other discussion points
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It's essential to know how much payload is in the drug.
It was acknowledged that you will likely need to perform some nonclinical studies on your
payload alone, which will establish a safety profile.
From a weight/weight basis, the amount of free drug in the product is likely very minimal
(below ICH threshold for safety).
A FDA participant mentioned that the Toxicology Reviewers are likely to look closely at
what is going on in clinical studies throughout industry.
o For example, they could request a study to start at a lower dose because what they
have seen on other programs.
For drugs with highly active payloads, resulting in low therapeutic doses,
o Studies for compatability with infusion sets are difficult due to further dilution in
saline
o Developing analytical methods with the appropriate sensitivity level might be
difficult.
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It was acknowledged that some characteristics can be analyzed at mAb rather than at the
ADC.
If you establish a robust manufacturing process (with control) for the mAb, can you avoid
repeating characterization on the conjugated ADC?
o The participants felt that this would likely be a case-by-case decision.
It was mentioned that, when you're generating reference standards, make sure you're
already thinking about criteria for potency (e.g., binding ELISA).
o If there isn't transparency in providing reference standard information, there could
be difficulty in piecing the analytical (e.g., potency) story together.