ADCs: What are they and why do they matter?

Terry Chapman, University of Bath PhD Student, Bath ASU Researcher

Introduction

Monoclonal antibodies (mAbs) have been a healthcare success for over two decades, significantly improving cancer therapy, but may be superseded by antibody drug conjugates (ADCs). So what are ADCs and why do they matter?

This is the first article in a series of five blog posts that will put the ADCs in the spotlight. This article will summarise ADCs while four subsequent posts will go into more depth. Look out for; ADCs: Function & Pharmacology, ADCs: Pros & Cons, ADCs: Origin & Obstacles, and ADCs: Pipeline & Progress.

ADCs are a new and important class of drugs, essentially monoclonal antibodies with cytotoxic compounds linked to them, known as payloads. By targeting potent payloads, ADCs are likely to quickly transform the cancer therapy landscape.

General Principle

ADCs are formed from three important moieties, each as functionally important as the other. The warheads provide the core cytotoxicity. The linkers conjugate warheads to mAbs and control payload release. The mAb provides targeting, delivery and mAb specific cell interactions, e.g. Antibody dependent cell mediated cytotoxicity.

ADCs bind to target antigens, typically tumour specific or selective receptors, via the variable domains of the mAb. The ADC-antigen complex is then internalised into  the target cell. It is trafficked eventually to a lysosome which denatures the ADC-antigen complex via acidic pH, proteases and other acid hydrolases. These conditions release the cytotoxic payloads which are then free to move to their site of action and exert their toxic effect.

This mechanism leads to rapid accumulation of active cytotoxic payloads within a target cell population, while keeping systemic levels of the active cytotoxic compound to a minimum. The payloads are untargeted, and are up to 4,000 times more potent than currently licensed cytotoxic compounds, so this is critical for patient safety.

Licensed Products

Brentuximab vedotin and trastuzumab emtansine are two currently licensed ADCs. Brentuximab vedotin treats hodgkins lymphoma and anaplastic large cell lymphoma.  Trastuzumab emtansine treats HER2⁺ breast cancer. A 2014 study [1] published in the Lancet demonstrated trastuzumab emtansine outperformed the physician’s choice for recurrent or metastasized HER2+ breast cancers with over 31% higher progression free survival rate, and 11% fewer  grade 3 or higher events, over 14 months.

Stability

ADCs are heterogeneous by nature; they can have between zero and twelve payloads. The number of payloads is referred to as the drug antibody ratio (DAR). DAR has a significant effect on the therapeutic effect, innate stability and pharmacokinetics. Location of payload binding is referred to as distribution of payloads (DOP). DOP can vary between ADCs with the same DAR. DOP could affect the therapeutic activity of an ADC.

Generally the higher the DAR the more potent but less stable and more rapidly cleared an ADC is. DOP can vary even between two ADCs with the same DAR. DOP can affect therapeutic activity, if payloads have bound in location that reduces binding or antibody dependent actions.

ADCs are likely to undergo a complex degradation cycle. In addition to the combined degradation for mAbs and small molecules, they will demonstrate varying average DAR resulting in a fluctuating non-linear rate of degradation. Furthermore, linker degradation will result in free payload leading to unacceptable toxicity.

These are just some of the key differences that highlight why ADCs should not be treated like existing mAb therapies, especially concerning efficacy, stability and shelf life.

References

1. Krop IE, Kim SB, González-Martín A, LoRusso PM, Ferrero JM, Smitt M, Yu R, Leung AC, Wildiers H; TH3RESA study collaborators. Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Jun;15(7):689-99.