Antibody-drug conjugation (ADC) technology has been around for several decades but has yet to reach its full potential in terms of clinical success. In this second article, Penelope Drake and David Rabuka, of Catalent Biologics, discuss how the learning curve of recent years is opening a promising way forward for ADCs. The first article of this series was published online in August 27, 2018.
One of the factors that has held back the wider use of ADCs as therapeutics is the difficulties encountered in striking a balance between payload efficacy and dose-limiting toxicities in off-target tissues. According to a survey of papers in the literature where ADCs with the same linker/payload but different drug-to-antibody ratios were dosed such that the amount of payload delivered was held constant but the amount of antibody varied, it appeared that dosing with more antibody resulted in improved efficacy.[1] This improvement may have been due to better ADC tumor penetration, which in turn may point the way towards improving efficacy outcomes without dosing more drug, thus widening the therapeutic window. If this is the case, then there are implications for preclinical, and perhaps clinical, study design.
Another area that is gaining increasing attention is the potential of the adaptive immune system to augment or complement in vivo efficacy of ADCs, particularly with respect to testing combination therapies of ADCs dosed along with checkpoint inhibitor drugs.[2] Given that many ADC payloads induce immunogenic cell death in their targets, there are distinct possibilities for synergy. There are also several examples of clinically-tested ADCs where clinical response was uncoupled from target antigen expression[3-5], suggesting that an innate immune-based mechanism may be at work.
Combination therapies
Combination therapies also merit further investigation, and in particular, combinations of drugs whose mechanisms of actions intersect with tumor biology have the potential to improve efficacy. For example, in recent work by Immunomedics, preclinical studies demonstrated a rationale for co-dosing an ADC along with small-molecule drugs that inhibit multidrug resistance (MDR) efflux activity in order to overcome ADC drug resistance due to tumor upregulation of MDR efflux transporters.[6]
The choice of target antigen will affect both the efficacy and toxicity of an ADC. A relatively new approach is to target the cancer stem cells or tumor-initiating cells (TICs) that propagate disease. Various biological markers exist for TIC identification, and two have been selected as ADC target antigens, with the furthest advanced of these being delta-like protein 3 (DLL3), recognized by the ADC rovalpituzumab tesirine, currently being tested in phase 3 clinical trials for the treatment of small-cell lung carcinoma.[7] Also being investigated as an ADC target is the protein tyrosine kinase 7 (PTK7), expressed on TICs isolated from patient-derived tumor xenografts (PDX) representing several solid tumor types. The ADC caused tumor growth inhibition in several PDX models and was also shown to reduce the frequency of TICs in tumor tissue over time.[8]
Another novel approach to controlling tumors is to limit their blood supply by targeting tumor-specific vasculature. For example, the antigen CD276 is expressed on both tumor cells and tumor endothelial cells in some cancers, but not on endothelium in healthy tissues. It has been hypothesized that an ADC that simultaneously eliminates both populations within the tumor environment would yield greater overall tumor control.[9]
Recent advances in linker technology could also improve the success rate of ADCs. The linker plays a vital role in joining the antibody to the small molecule payload, as it must be stable during ADC circulation within the bloodstream without compromising biological potency. The structure of the payload will dictate which reactive chemical groups may be used for ligation, with primary and secondary amines currently being most commonly accessed. Research continues to broaden functional group accessibility in this field.
Traceless linkers
Payloads that lose biological potency when the core chemical structure is modified require the use of traceless linkers. These systems consist of a cleavage event (the trigger) followed by the self-immolation event that releases the free payload. The kinetics of both cleavage and immolation can vary according to the structure of the linker and payload.
For payloads that tolerate chemical elaboration, non-cleavable linkers offer an opportunity to adjust payload functionality. For example, work has been carried out on a triglycyl peptide linker designed to overcome some of the biological limitations currently imposed on the efficacy of non-cleavable conjugates. [10] The work aimed to limit the extent of lysosomal proteolysis required for payload liberation, improve payload transit from the lysosome into the cytosol, and hinder payload transit from the extracellular space into neighboring cells. Use of the triglycyl design effectively turned the linker into a cleavable, but not traceless, system that was uncharged at low pH (in the lysosome) but negatively charged at neutral pH (in the cytosol). The study highlights some of the complex biology that underlies successful delivery of a cytotoxic payload to its site of action within a target cell.
Improving linker stability
A consensus is growing in the field that the conjugation site can affect the biophysical and functional outcomes of ADCs. It is a known effect of site-specific payload placement that conjugation at certain positions can improve linker stability, with the hypothesis being that particular conjugation environments can “shield” the linker from access to enzymatic activity such as proteases and esterases. Recent work carried out by Pfizer using site-specific conjugation of a new spliceostatin payload, thailanstatin A, at a range of locations revealed that the activity of this particular payload is unusually dependent on the conjugation site. [11] Studies are underway to explain this phenomenon.
ADCs have yet to live up to their full clinical potential, but many more tools are now available to optimize their development. These include fully human/humanized monoclonal antibodies, site-specific conjugation approaches, a range of potent cytotoxic payloads with various mechanisms of action, versatile linker technologies, and sophisticated analytics. Some ADCs currently in later stages of the clinical pipeline have shown encouraging results and may lead to additional approvals in the near-term.
Beyond oncology
It should also be noted that the therapeutic areas of opportunity for ADCs are not limited to oncology. For example, an antibody-antibiotic conjugate has been shown to be more effective than the free antibiotic payload for treating infections caused by drug-resistant bacteria. [12] ADCs and related conjugates could also help to improve treatment of chronic conditions, such as autoimmune and cardiovascular diseases, by using selective payload delivery to reduce side-effects.
Technologies are also on the horizon that aim to achieve targeted drug delivery in the absence of an internalizing antigen. One such approach involves the use of cytotoxic payloads that can induce cell death by mediating signals at the cell surface. [13] Another involves a two-step drug-delivery method whereby the targeting and delivery steps are functionally and temporally uncoupled; initially an antibody against a non-internalizing target antigen delivers the payload to the cell surface, then the payload release is induced by a systemically-delivered small molecule. [14]
Based on these innovations, it is only a matter of time until creative solutions find their way into the clinic, leading to a new and exciting phase of ADC therapeutics.
How to cite:
Drake P, Rabuka D, ADCs – Look Forward to a Potent Future (2018),
DOI: 10.14229/jadc.2018.09.27.001.
Original manuscript received: July 25, 2018 | Manuscript accepted for Publication: August 21, 2018 | Published online September 27, 2018 | DOI: 10.14229/jadc.2018.09.27.001.
Last Editorial Review: September 26, 2018
