Antibody Drug Conjugates Q&A: A Novel Approach to Drug Delivery in Oncology

What is an antibody drug conjugate?

An antibody drug conjugate, or ADC, is a drug modality that consists of three main components: an antibody, a linker, and a drug, often referred to as a “payload” due to its cytotoxic nature. The antibody is a protein that binds to a specific antigen, or protein, which is expressed on the surface of tumor cells. The linker is a chemical bond that connects the antibody to the payload. The payload is typically a small molecule cytotoxic agent that can kill cells once released inside the tumor cell.

What are the advantages of ADCs over conventional drug delivery methods?

ADCs have several advantages over conventional drug delivery methods. First, ADCs can deliver a higher dose of a cytotoxic agent to tumor cells, while reducing the exposure and toxicity to normal cells. This is because the antibody acts as a homing device that guides the drug to the tumor cells, and the linker acts as a gatekeeper that releases the drug only inside the tumor cells. This way, an ADC can reach a higher therapeutic index, which is the ratio of the effective dose to the toxic dose. Second, ADCs can overcome some of the resistance mechanisms that tumor cells develop to evade conventional drugs. This is because an ADC can bypass some of the barriers that prevent the drug from reaching the tumor cells, such as the blood-brain barrier, the tumor microenvironment, and the efflux pumps. Moreover, an ADC can target multiple pathways that are involved in tumor growth and survival, such as apoptosis, angiogenesis, and cell cycle.

What are the main challenges and limitations of ADCs in terms of finding the optimal combination of antibody, linker, and drug?

The antibody should have high affinity, specificity, and internalization rate for the target antigen. The linker should have high stability in the bloodstream, but low stability in the tumor cell. The drug should have high potency, solubility, and stability. The combination should also have a suitable drug-antibody ratio (DAR), which is the average number of drug molecules bound to each antibody molecule. The DAR affects the efficacy and safety of an ADC. Too low, and an ADC may lose its potency. Too high, and an ADC may exhibit more toxicity, calling into question its safety.

What are some stability and safety considerations?

An ADC should be stable enough to maintain its integrity and activity during storage, transportation, and administration. However, an ADC may undergo degradation, aggregation, or deconjugation due to several factors, such as temperature, pH, light, and enzymes. These changes may affect the quality, potency, and safety of an ADC. Therefore, an ADC should be carefully monitored and controlled for its stability and safety throughout its synthesis and use.

Can you elaborate on the critical role of analytical services in the quality assurance of antibody drug conjugates (ADCs)?

Analytical services are the cornerstone of quality assurance for ADCs. They delve into ADCs’ reactions under physiological conditions and ascertain key metrics like serum stability and DAR. These metrics are vital for evaluating ADCs’ fitness for clinical applications. By providing a window into ADCs’ pharmacokinetics and stability, analytical services ensure that only ADCs with the most promising profiles proceed to therapeutic use.

In what way do serum stability studies enhance the quality evaluation of ADCs?

Serum stability studies are a window into the future performance of ADCs within the human body. They simulate the human physiological environment to assess how ADCs will fare over time, which is pivotal for confirming their structural integrity and therapeutic action over their entire shelf life and dosing schedule.

What are the current strategies for analyzing ADCs in biological matrices for pharmacokinetics (PK) and toxicokinetics (TK)?

Analyzing ADCs in biomatrices for pharmacokinetics (PK) and toxicokinetics (TK) involves a multifaceted approach due to the complex nature of ADCs, which consist of an antibody linked to a cytotoxic drug. Current strategies typically employed include various separation and detection techniques, such as Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) and immunoassays. LC-MS/MS is widely used for quantifying small molecules and the drug conjugated to the antibody, offering high sensitivity and specificity for detecting both free and conjugated forms in biological matrices. Immunoassays, including enzyme-linked immunosorbent assays (ELISA) and electrochemiluminescence assays, are commonly used for detecting and quantifying the antibody component of ADCs. Additionally, hybrid LC-MS/MS/Immunoassay methods combine the strengths of both techniques to enhance sensitivity and specificity, with immunoassays capturing an ADC or its components for subsequent LC-MS/MS analysis.