Theo de Boer, PhD, principal scientist - scientific director LCMS, Ardena shares the key steps to bring ADCs successfully to clinical trial.
Ardena
The use of antibody-drug-conjugates (ADC) in drug development is becoming more and more widespread, thanks to their potential to improve the effectiveness of cancer treatments by enabling more precise targeting of cancerogenic cells. ADCs harness a mechanism based on an antigen-mediated uptake of a cytotoxic drug, which is then released directly into target cancer cells - by achieving this while avoiding healthy cells, they enhance efficacy with reduced adverse side effects.
There are currently 14 ADCs approved by regulators worldwide, demonstrating their value in creating oncological drugs that not only offer improved performance, but reduced toxicity too.
Recent research suggests that there is more that can be done to further enhance ADC efficacy and reduce negative effects - with the possibility for greater improvements in precision cell targeting.
Development challenges
ADCs pose development challenges. They are complex molecules, consisting of a number of components:
- A cytotoxic payload
- A target-specific antibody
- A covalent linker that joins these two elements together.
ADCs also have a narrow therapeutic window, and their effectiveness can be negatively impacted by undesired toxicity caused by metabolic instability, poor pharmacokinetics, or off-target effects.
Careful characterisation is vital to mitigate this risk. In-vitro and in-vivo assessment prior to first in human studies, can help predict the impact of ADCs’ inherent heterogeneity and potential anti-drug antibodies on their pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy.
This can help identify the multiple elements of an ADC: the total antibody content, the antibody conjugated with at least one payload, the free payload, and the total conjugated drug. It can also support the investigation of the presence of anti-drug antibodies (ADAs).
Developing the ideal bioanalytical strategy
A comprehensive bioanalytical strategy created at the beginning of a project is vital to carry out the characterisation needed to overcome the challenges of ADC development and to deliver an effective finished therapeutic.
By following several key steps, it is possible to develop an effective strategy to maximise the chances of project success:
Step 1: Consider how to detect unwanted elements in the formulation: When designing a bioanalytical approach for ADCs, it is essential to consider the detection of the antibody, fully and partially conjugated antibody, off-target conjugated antibody, unconjugated drug, drug-conjugate metabolic stability, pharmacokinetics, and potential immunogenicity. Detecting ADCs and their components in biological fluids can be particularly challenging due to the complexity of the matrix.
Step 2: Use a case-by-case scientific approach for selecting effective analytical methods: Standard analytical methods for bioanalytical characterisation of proteinic, chemical, and immunogenic components do not exist. The availability of specific reagents and equipment should be considered during the design of the bioanalytical method, and the bioanalytical platform should not prejudice the strategy.
Step 3: Select an appropriate technology for ADC assays: This requires a high degree of expertise and in-house capabilities. For instance, liquid chromatography (LC) can be operated in different ways to separate chemical and/or biological components from a variety of ADC samples, especially when paired with a mass spectrometer (LC-MS/MS). The ligand binding assay (LBA) platform can also be used. Under this method, the receptor and/or one or more ligands are tagged or labelled to qualify and quantify the substrate of interest by measuring the intensity of the signal emitted by the complex.
Step 4: Choose the right reagent: Analytical procedures for ADCs require highly specific and highly sensitive reagents compared to standard analysis. The anti-idiotype antibodies which target the variable regions of antibodies must be identified and produced in sufficient quantities for each development program. Anti-idiotype antibodies represent the antigenic region specific for the antibody and are required for ADC selective PK and immunogenicity (ADA) analysis.
Step 5: Don’t forget about regulatory compliance: The European Medicines Agency (EMA) and the Food and Drug Administration (FDA) have provided regulatory expectations for antibody therapeutic entities. Recently, additional guidelines were drafted with an emphasis on the importance of PK and immunogenicity assessments. All data and investigations must consider the requirements for IND/IMPD submission, approval, and the first clinical study.