Summary

G protein-coupled receptors (GPCRs) are a large family of proteins that play important roles in human health and disease. Roughly one third of all approved medicines work by targeting a GPCR however, historically none of these medicines have been monoclonal antibodies.

Recent advances in antibody technologies have seen a surge of GPCR directed biopharmaceuticals being developed and tested, leading to the first approvals of GPCR directed monoclonal antibodies. Here we review the background to GPCRs and the development status of GPCR targeting biopharmaceuticals.

Structure and function of G-protein-coupled receptors.

G proteins cross the cell membrane seven times. In unstimulated cells, the state of G alpha (orange circles) is bound with GDP, G beta-gamma (purple circles), and a G-protein-coupled receptor (GPCR; light green loops). Upon receptor stimulation by a ligand the state of the receptor changes. G alpha dissociates from the receptor and G beta-gamma, and GTP is exchanged for the bound GDP, which leads to G alpha activation. G alpha then goes on to activate other molecules in the cell. Image credit: Li, J. et al. The Molecule Pages database. Nature 420, 716-717 (2002).

GPCRs as therapeutic targets

GPCRs regulate a range of cellular processes that are critical for cancer including cellular proliferation, chemo-resistance, self-renewal, apoptosis, stress signalling, immune evasion, invasion, angiogenesis and metastasis. GPCRs can regulate many intracellular signal transduction pathways relevant to cancer cells including EGFR/Ras (proliferation), ATF4/CHOP (cellular stress), chemokine (metastasis) and p53 (apoptosis) mediated signalling.

From analysis of cancer genomes, it is suggested that GPCR mutations are found in about 20 percent of all cancers. GPCRs have been largely overlooked in oncology drug discovery efforts as this mutation rate is less frequent compared to other oncology pathways. Currently however there is increased interest in the idea that pharmacological targeting of GPCRs could provide an opportunity to block tumorigenic signals.

Because GPCRs play such a wide variety of roles in the body, further therapeutic areas in which GPCRs are relevant to include psychiatric disorders, diabetes and obesity, cardiometabolic disorders, irritable bowel syndrome, graves’ disease, migraine, inflammation, hypertension, neuropathic pain and chronic infection.

GPCR directed biopharmaceuticals in clinical trials.

GLP-1R is the glucagon-like peptide 1 receptor, ETA is the endothelin receptor A, GCGR is the glucagon receptor, C5AR1 is a receptor for complement C5A, FZD are frizzled receptors, CCR8 is a chemokine receptor, IND (investigational new drug) clearance allows clinical trials to begin.

Conclusion

Improvements in antibody technologies have seen G-protein coupled receptors become a tractable target for biopharmaceutical therapies such as monoclonal antibodies. This opens a massive opportunity for drug development in several therapeutic areas.

GPCRs are already the target of a third of all approved medicines yet these drugs currently target roughly one tenth of the GPCR family of proteins, suggesting many more therapeutic targets exist. The development of GPCR targeted biopharmaceuticals will lead to new treatments for an array of diseases and the three molecules already approved represent the tip of an iceberg.

Alzheimer’s disease

It is easy to see why big Pharma has focussed and invested so heavily to develop therapies for Alzheimer’s disease (AD). The disease is the most common cause of dementia, not a normal part of aging, and presents a major health issue with the patient population only set to grow.

This is currently an incurable neurodegenerative disease mostly affecting elderly people, although an early-onset form can also affect younger people. In both cases, it is characterised by progressive dementia leading to loss of autonomy and ultimately death. In short, the effects are devastating to both the patients and their families.

Alzheimer’s and the brain: A tale of two proteins

In 1906 Dr Alois Alzheimer described microscopic changes in the brains of affected patients now called plaques and tangles, which are caused by changes in two proteins: Beta amyloid and Tau respectively.

Plaques and tangles are thought to play a critical role in disrupting the communication between nerve cells and the processes they need to survive. Given the limited availability of data in humans however, it has been difficult to understand whether these changes are a cause or symptom of AD.

Results from animal models have suggested that targeting these proteins with monoclonal antibodies could be effective in slowing or reversing the macromolecular changes in brain architecture. However, translating these results to therapies in humans, with the hope that this will be effective in slowing or preventing cognitive decline, has proved hard work.

Dozens of clinical trials of monoclonal antibodies results have shown results that are disappointing or mixed at best. Aducanumab did achieve marketing approval from the Federal Drug Agency in the United States in 2021 although that decision was controversial, and the European Medicines Agency refused to allow it, doubting its effectiveness.

How is lecanemab different?

Lecanemab differs from other monoclonal antibodies in late-stage clinical trials for AD in two important ways: its structure and target. Firstly, where other antibodies have two binding sites (bivalent) lecanemab has been carefully engineered to have six binding sites (hexavalent).

The novel structure of the antibody increases its size from the regular 150 kDa to around 250 kDa but also increases its strength of binding to the target, possibly due to a reduced rate of dissociation from it. A more in-depth description of the structural features and avidities of lecanemab has been published by its designers if you want to read more [1].

Figure 1: Amyloid beta proteins exist in different forms that can aggregate progressively to create structures called plaques in the brain. Similar changes occur in Tau proteins. Secondly, although many drugs (including aducanumab) target beta amyloid (Aβ) protein, lecanemab was generated specifically against synthetic Aβ protofibrils.

Aβ proteins can exist in several forms including soluble monomers which aggregate progressively to form oligomers, through protofibrils and then insoluble fibrils, as represented in Figure 1. Protofibrils are soluble aggregates of Aβ monomers between 75 and 5000 kDa in size that are thought to be key pathogenic forms of the protein responsible for synaptic and neuronal degeneration in AD.

Laboratory comparisons between lecanemab, aducanumab and gantenerumab have shown that lecanemab has the strongest binding affinity for Aβ protofibrils of them all. It has been suggested that rather than binding plaques directly, lecanemab is most effective through depletion of soluble Aβ protein in the brain. This leads to a shift in the equilibrium between different forms of Aβ, causing more protein to solubilise off plaques.

Work(s) in progress

Although lecanemab is a clear step forward for AD therapies much more research remains to be done in areas that could bring additive or synergistic improvements, for example: What about Tau? Clinical trials using both antibodies and vaccines that target Tau fibrils are currently on-going. Additionally, some studies are testing antibodies that target both Aβ and Tau pathology, due to the similarity of their abnormal oligomer form. Antibodies in the brain: The blood brain barrier normally prevents large molecules from reaching the central nervous system, meaning only a fraction of infused antibodies reach their target in the brain.

The use of alternative technologies such as generation of microbubbles via focused ultrasound, or new antibody formats such as bispecific antibodies, could help deliver antibodies to their target. Diagnostics: Most clinical symptoms of AD appear years after the development of internal signs of disease such as plaques and tangles.

This means diagnosis is (too?) late, which may partly explain the inefficiency of current treatments. Work to improve early diagnosis, for example by developing new biomarkers would be helpful. Minimising side effects: Severe side effects, including vasogenic oedema and microhaemorrhages, attributed to bapineuzumab’s Fc effector function caused clinical trials to be terminated. Engineering of antibody Fc regions to silence this function could prevent side effects.

Conclusion

Results from clinical trials have shown lecanemab’s potential to slow cognitive decline in Alzheimer’s patients. Excitement surrounding the data comes in part from the fact that this is the first clear demonstration that targeting the formation of plaques in the brain will be an effective therapeutic strategy. Lecanemab is not a “magic bullet” or the end of the story, but a clear step toward effective AD therapies that are desperately needed by patients and their families.

The rules for naming monoclonal antibodies have changed…

INTRODUCTION

The first monoclonal antibody to achieve marketing approval was Muromonab in 1986. Since then, monoclonal antibodies have become one of the most successful classes of current medicines bringing new therapies for cancer, immune diseases and a growing number of other indications.

Despite the success of monoclonal antibodies in the clinic, some of the nuances of this class of therapeutics can be poorly understood. To improve wider understanding of these complex therapeutics, this is a brief review of the rules and meanings of antibody names and the latest changes that mean there will be no more “mabs”.

NAME STRUCTURES

Although the names given to antibodies can seem confusing at first, there is a structure hidden within them.
In 1995, the international non-proprietary name (INN) expert group of the World Health Organization (WHO) published rules for naming monoclonal antibodies to ensure that every name was globally recognised and unique to a single product. Each name is organised with a prefix- two substems and a stem (as represented in the example below) and these morphemes convey specific information about the protein.

The prefix itself does not follow any specific criteria but is unique for each product. The target substem (also called substem A) specifies the target of the antibody such as a tumour or bacteria. The source substem (B) relates to the species from which the monoclonal antibody was derived, so antibodies that were derived from a mouse for example would contain the substem “o”. The stem or suffix “mab” has been common for all monoclonal antibodies. The different parts of antibody names are further explained below.

STEM

This is the part of the product name that will change in the most noticeable way following changes to naming rules issued in late 2021. Until now, all antibodies have been easily identified by the “mab” stem, with only rare exceptions (muromonab being one example).

The latest update of the naming rules from the INN expert group replaces “mab” with four alternative names. This expanded collection of name stems has been introduced to accommodate the increasing number of antibodies, to decrease sound-alikes, and to provide information about modifications to the immunoglobulin structure.
These changes reflect the increasing importance of our understanding of how antibodies interact with different components of the immune system, and how genetic engineering of their fragment crystallisable (Fc) regions can modulate those interactions for therapeutic benefit.

For example, some Fc regions can be changed to increase functional activities such as antibody dependent cellular phagocytosis (ADCP). Alternatively, where the purpose of the antibody is to block receptor interactions, such as PD-1 inhibitors, or to bind and neutralise a protein, the antibody may be modified to decrease such functional activity. The four new name stems are explained further below.

SOURCE SUBSTEM

For antibodies named until early 2017, the source substem relates to the animal from which the antibody was obtained.

Early monoclonal antibodies were produced in mice (substem “o”, yielding the ending -omab) or other non-human organisms. These products had the potential to induce anti-drug antibodies in the patient, making the therapies less effective over time.

Subsequent development of antibodies has seen a trend toward more humanised products that are less immunogenic. This can be achieved by replacing parts of the antibody with human amino acid sequences, or pure human antibodies can be engineered.

If the constant region is replaced with the human form, the antibody is termed chimeric and the substem “xi” was used. Part of the variable regions may also be substituted in which case it is called humanised and “zu” was used.

In theory, antibodies could be produced from rats (“a”), hamsters (“e”) or primates (“i”), although no products derived this way ever applied for a non-proprietary name. As part of the revision of antibody nomenclature the source substem will no longer be included in new names, reflecting the trend toward humanised and fully human antibodies.

TARGET SUBSTEM

The substem preceding the source of the antibody refers to the medicine’s target, or the epitope to which the antibody binds. Examples are tumours, organ systems like the circulatory system, or infectious agents like bacteria or viruses.

In the naming scheme as originally developed, these substems mostly consisted of a consonant, a vowel, then another consonant (-thanks Rachel!). The final letter could be dropped if the resulting name was difficult to pronounce.

Examples of target substems include -ci(r)- for the circulatory system, -li(m)- for the immune system (lim stands for lymphocyte) and -ne(r)- for the nervous system. The final letter was usually omitted if the following source substem begins with a consonant (such as -zu- or -xi). Combination of target and source substems resulted in endings like -limumab (immune system, human) or -ciximab (circulatory system, chimeric).

New and shorter target substems were adopted in 2009. They mostly consist of a consonant, plus a vowel which is omitted if the source substem begins with a vowel. For example, human antibodies targeting the immune system receive names ending in -lumab instead of the old -limumab.

Some endings like -ciximab remained unchanged. The old system employed seven different substems for tumour targets, depending on the type of tumour. Because many antibodies are investigated for several tumour types, the new convention only has -t(a)- to denote a tumour target. With the source substem being discontinued in 2017, the need for dropping the final vowel of the target substem disappeared.

CONCLUSION

The non-proprietary names given to monoclonal antibodies can appear random but do follow a defined structure and rules that can change every few years.

Since the early antibodies entered the clinic, improvements have been made to make these products even more effective as therapies. These changes are reflected in the latest rules of the system for generating non-proprietary names that will see the end of the “mab” stem.

Although no more products will have names ending in “mab”, monoclonal antibodies will continue to form the basis of many important and innovative therapies available to patients for years to come.

Summary

The success of protein-based drugs has seen them impact on almost every branch of modern medicine. They are useful modulators of the immune system and this power has been applied in the clinic to devise new cancer therapies with stellar success. Sirukumab is an immune modulator that dampens inflammatory responses by binding the protein interleukin-6. This has already proved effective in treating rheumatoid arthritis, however, a more radical study is examining the usefulness of sirukumab in treating depression.

This approach could open up a whole new field of drug development for further psychiatric conditions, including bipolar disorder, anxiety disorders, and schizophrenia, which may be driven, at least in part, by excess immune activity affecting the brain.

Evidence linking Immune System to Psychiatry

Much of the work linking inflammatory processes to psychiatric illnesses stems from a startlingly obvious observation: everyone feels miserable when they are ill. Clinical and preclinical research over the last two decades has yielded a number of clues to support the notion that inflammation can indeed affect mood. For example, cytokines are a family of proteins that are key regulators of immune responses.

Both cytokines and inflammation show major increases in patients during depressive episodes, and in people with bipolar disorder, cytokine levels drop off in periods of remission. Healthy people can also be temporarily put into a depressed, anxious state when given a vaccine that causes a spike in inflammation. Further clues are found in people with inflammatory diseases such as rheumatoid arthritis since they tend to suffer more than average with depression.

Cancer patients given the cytokine interferon alpha to boost their inflammatory response and help fight the cancer, often become depressed as a side-effect. From all the biomarkers of inflammation whose expression has been associated with depressed mood, elevated IL-6 has been the most consistent.

A number of research groups have also found that many neuro-receptors are affected by autoantibodies. These include the NMDA, AMPA and GABA receptors, in addition to autoantibodies targeting the potassium channel VGKC, all of which have important functions in the brain.

Currently, there are over twenty neuro-receptors thought to be affected by autoantibodies whose identification can guide both diagnosis and treatment. Autoimmune brain disorders often respond dramatically to immunosuppressive therapy.

Psychiatry: a lack of new treatments

There is a dearth of new treatments for psychosis -there have been no major breakthroughs in the last fifty years, and big pharma has largely neglected the area. It is the same for depression which sees 350 million people suffering worldwide, with an estimated 30 to 60% of these patients not responding to any current pharmacological treatment.

In contrast, therapies targeting the immune system have seen heavy investment with a healthy pipeline of drugs already achieving market approval, or in late stage clinical trials.

Establishing a link between the immune system and psychiatric disorders, therefore, offers the opportunity to borrow from this success, avoiding heavy drug discovery costs. An example is sirukumab, a monoclonal antibody that binds and neutralises the cytokine IL-6. This cytokine has many functions within the immune system depending on which cell type it is acting upon (see figure above). Sirukumab was originally intended for the treatment of the autoimmune condition rheumatoid arthritis where it has proved a safe and effective medicine.

A clinical trial is now underway to assess whether sirukumab is useful as an adjunctive therapy for patients with major depressive disorders. If successful this study will drive further research into the interface between the immune system and psychiatry that should encourage and inform more sophisticated interventions.

It is tempting to think that the cohort of patients with depression who do not respond to current therapies are the same patients who show excess activation of the immune system. It is unlikely, however, that anti-inflammatories will become the doctor’s first approach to treating depression.

Many questions remain to be answered: Which are the biomarkers of inflammation that could guide effective treatments? Why don’t all patients with autoimmune conditions become depressed? What are the triggers of depression following inflammation? Questions such as these will need to be answered before we can fully exploit the findings in this nascent field.

Conclusion

If successful the sirukumab clinical trial will demonstrate a link between the immune system and mood in patients with major depressive disorders, driving further research. Confirmation that a subset of what we currently diagnose as primary psychiatric disorders, result from amenable immune conditions would open a route to new treatments from the immune modulators that are already available.

In addition, the recognition that psychiatric conditions can result from imbalances throughout the body, rather than just the mind, may serve to dispel some of the stigma surrounding these conditions, and that alone would be welcomed by patients.

Dr Benjamin Young and Terry Chapman spoke at the annual NHS QA Symposium on 15th September 2015. These are the slides from their talk.

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

Introduction

This is the fifth article in a series of five blog posts that are putting ADCs in the spotlight. This article will describe ways in which third generation ADCs may improve upon current ADCs. Please read the introductory post ‘ADCs: What are they and why do they matter?’ before this post, if you are unfamiliar with ADCs.

Future Development

ADCs, like trastuzumab emtansine and brentuximab vedotin, are a clinical success and demonstrate ADCs are worth developing beyond their current limitations and expanding on their advantages.

A key problem for ADCs is that they have heterogeneous DAR and DOP. Current ADCs have an average DAR of 3 or 4, an ideal DAR for pharmacokinetics, efficacy & stability but range from 0 to 12. High DAR negatively impacts on pharmacokinetics and a low DAR is less efficacious. Heterogeneity, due to variable linker attachment, results in more expensive, less effective therapies.

One way being investigated to tackle this problem is site specific conjugation (SSC). Linkers are attached to engineered cysteines or non-natural amino acids. These are engineered into the mAb which allows control of location and number of possible attachment sites. Research into SSC reports: improved serum stability, pharmacokinetic properties and comparable efficacy/toxicity profiles. SGN-CD33A is a site specifically conjugated ADC currently in phase 1 clinical trials for the treatment of acute myeloid leukaemia.

A second problem for ADCs is that they must release their payloads inside cancer cells. This involves finding a cancer specific or selective receptor that is internalised upon binding. These requirements clearly limit the number of possible receptors to target. Target identification previously used for mAbs included therapeutic activity assays. ADCs don’t require  a therapeutic response from receptor binding, just that the receptor is internalised. This means that receptors previously dismissed for mAbs may become viable ADC targets.

Other approaches are also being used to increase the number of targets such as initiating localised non-specific cytotoxicity. ADCs like epratuzumab-SN-38, that continuously release their payloads at a slow rate, are being investigated, if successful ADC internalisation wouldn’t be necessary as payloads are released in the micro tumour environment and can diffuse into and out of nearby cells.

This approach could overcome heterogeneous solid tumour receptor expression by ensuring tumour cells that no longer express the extracellular receptor are still exposed to the cytotoxic warhead.

ADCs are huge molecules, they suffer from poor penetration in solid tumours so can’t treat them effectively. One way to improve their penetration is reduce their size. Rather than using a complete antibody, single chain antibody fragments (scFv) or fragment antigen binding region (Fab) have been tested and are able to selectively target and deliver cytotoxic payloads to tumour cells in vivo. These have their own drawbacks such as reduced serum half-life and no Fc mediated effects, but are a viable way to develop ADCs into effective therapeutics for solid tumours.

Many ADCs in development and in addition to the licensed ADCs use payloads that are substrates for drug-efflux pumps. This is problematic for ADCs and helps explain why the payloads must be so potent. Scientists have already however, made payloads that are not substrates for common efflux pumps. DM4 has comparable therapeutic activity to the trastuzumab emtansine warhead DM1, but is unaffected by the common drug efflux pump p-glycoprotein pump.

The linker can also affect whether the payload will be effluxed by a pump as demonstrated by Kovtun (2010) who compared non polar to highly hydrophilic linkers while retaining the same payload. Kovtun found that the hydrophobic linker reduced efflux and therefore increased efficacy of the ADC. If we can prevent efflux affecting ADC payloads we would be able to use less ADC or less potent payloads, reducing off target effects and increasing the therapeutic window. SGN-CD33A is resistant to the most common multi drug resistance pump, MDR1, as well as having site specific conjugation.

Summary

ADCs are past a critical point in their development. They have been demonstrated as more effective than conventional therapies, but still have obvious limitations, such as heterogeneous conjugation chemistry, restrictive target receptor characteristics, poor penetration, or rapid drug efflux.

There are many proposed ways to overcome these limitations, such as site specific conjugation, novel drug release mechanisms, use of Fabs or scFvs instead of complete antibodies and efflux pump resistance payloads and linkers respectively. With over 40 ADCs in phases one to three, expect to see far more licensed ADCs in the near future, and as the drug class improves I expect it will begin being used to treat diseases other than cancer.

References

1. Kovtun YV, Audette CA, Mayo MF, Jones GE, Doherty H, Maloney EK, Erickson HK, Sun X, Wilhelm S, Ab O, Lai KC, Widdison WC, Kellogg B, Johnson H, Pinkas J, Lutz RJ, Singh R, Goldmacher VS, Chari RV. Antibody-maytansinoid conjugates designed to bypass multidrug resistance. Cancer Res. 2010 Mar 15;70(6):2528-37.

Introduction

This is the fourth article in a series of five blog posts that are putting ADCs in the spotlight. This article will describe the origins of and obstacles faced during ADCs development from the beginning of the 20^th century to today. Please read the introductory post ‘ADCs: What are they and why do they matter?’ before this post, if you are unfamiliar with ADCs. Look out for ‘ADCs: Pipeline & Progress’.

Conjugating toxic compounds to antibodies was first proposed by Paul Ehrlich at the beginning of the 20^th century but scientific understanding and available technology was not sufficient to synthesis ADCs. Initial work by Kohler and Milstein [1] in the 1970’s paved the way for other scientists to begin selectively culturing monoclonal antibodies.

Additional key concepts required for a successful ADC were learned during the 1980’s and 1990’s as a result of investigating why the first generation of ADCs did not work as expected.

Key Concepts

Early ADCs used murine or chimeric antibodies. These are recognised as foreign entities by the immune system which raises an immune response. This leads to removal of many ADCs from the blood stream before they can deliver their payloads consequently reducing the concentrations attainable and duration of efficacious therapy. The immune response also causes side effects such as: rash, flu-like syndrome, systemic inflammatory response syndrome or anaphylaxis. To avoid unacceptable levels of immunogenicity, mAbs used in ADCs should ideally be humanized or human. , for example The monoclonal antibody rituximab or the ADC brentuximab vedotin are however chimeric antibodies and although weakly immunogenic are still useable.

Initial attempts at creating ADCs were targeted to receptors that were not selective enough to tumours, resulting in unacceptable toxicity.  Another problem was use of linkers that were not stable enough, leading to high levels of payload dissociation while still in circulation resulting in non-selective cytotoxicity. Linker instability was still a problem in the 2000’s as gemtuzumab ozogamicin (GO) releases 50% of its payloads over 48 hours in circulation. Due to this design flaw GO increased fatality rate, compared to alternative therapies. Licensed ADCs use linker chemistry that is extracellularly stable and cleaved or degraded intracellularly.

First generation ADCs were envisaged to target conventional chemotherapeutics to tumour sites. Due to the complex internalisation process, ADCs attain low concentrations of the administered warheads at tumour sites. Conventional agents are not therapeutically effective at the intracellular concentrations generated by ADCs, to compensate second generation ADCs use payloads up to 4000 times more toxic, such as mertansine, than conventional chemotherapeutics, such as doxorubicin.

Looking Forward

Key concepts such as mAb immunogenicity, linker stability and payload potency have been learned from first generation and early second generation ADCs. Trastuzumab emtansine incorporates the most currently held key concepts, incorporating potent payloads and stable linkers that degrade intracellulary and specific internalising target receptors. It is demonstratably therapeutically superior to other existing therapies for metastatic HER2+ breast cancer. The development of ADCs has been an arduous task with abundant obstacles. The outcome however has developed into a new and effective drug class.

References

Köhler G, Milstein C. 1975. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 975 Aug 7;256(5517):495-7.

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

Introduction

This is the third article in a series of five blog posts that are putting ADCs in the spotlight. This article will describe the pros and cons of the ADC drug class. Please read the introductory post ‘ADCs: What are they and why do they matter’ before this post, if you are unfamiliar with ADCs.

Look out for; ‘ADCs: Origins and Obstacles’, and ‘ADCs: Pipeline’, coming soon.

Pros

ADCs combine the targeting ability of mAbs with the cytotoxic power of small molecule drugs. ADCs are however, more than just the sum of their parts.

The high specificity of an ADC to its target receptor and combined with the controllable warhead activation and release mechanisms, result in ADCs having significantly less off target action compared to a therapeutically comparable small molecule cytotoxic. Consequently more patients are likely to tolerate ADC regimes. The higher specificity and controllable release mechanisms, ensure more drug successfully reaches the targeted cells, meaning lower concentrations are required to elicit an equivalent therapeutic response compared to antibody, small molecule co-therapy. These two principles give ADCs a wider therapeutic window, potentially making it useful in patients who can no longer tolerate combination therapy, or useful in patients who are no longer responding to combination therapy.

Resistance to ADCs takes longer to develop than resistance to their constituent mAb. Therry et al [1] reviewed methods of resistance to trastuzumab and lapitinib. While alteration or truncation of the HER2 extracellular domain could result in resistance to trastuzumab emtansine and trastuzumab, most methods of resistance to trastuzumab are due to changes in signalling downstream of HER2. Changes to signalling pathways would not prevent the payloads accumulating and destroying the cells. This means it should take longer for a relevant method of resistance to occur. The increased duration before resistance develops and wider therapeutic window, allow ADCs to fight cancers harder and longer than ever before, which accounts for the impressive therapeutic power of ADCs

Cons

ADCs are still subject to resistance, thus have a limited duration of effectiveness. ADCs must target extracellular receptors, that are endocytosed, to transport the payloads inside the cells. These extracellular receptors may not be exclusively found on the target cell population, while systemic activity may be low there could be unwanted toxicity at another population of cells that also has the targeted receptors present. Also multi-drug resistance pumps (MDRPs) actively remove released warheads. Mutations increasing MDRP expression, activity or reducing selectivity of MDRPs can increase the rate of developing resistance to ADCs.

ADCs are heterogeneous, with variable drug to antibody ratio (DAR) and distribution of payloads (DOP). This is because linkers bind to lysines or cysteines in the mAb which are present in greater abundance than payloads will bind. This increases potential variability in stability, pharmacokinetics and activity. ADCs with a DAR of 0 or 1 will reduce average potency, as they could bind in place of an ADC with a higher DAR. Furthermore certain DOPs will also have lower activity than others, potentially interfering with Fab or Fc region binding. The DAR and DOP variability increases the dose required for desired therapeutic effect, increases off target effects and increases the cost of therapy.

ADCs are also huge compounds, over 150kD, while conventional cytotoxics such as doxorubicin are less than 0.6kD. Their size makes it harder for ADCs to penetrate solid tumours, and less available at their intended site of therapeutic action.

Summary­­

ADCs have clear advantages over current mono and combination therapies, but also have clear disadvantages. The advantages demonstrably outweigh the disadvantages for trastuzumab emtansine in the treatment of HER2+ breast cancer. Expect more ADCs to be licensed as our understanding of this technology improves and allows us to diminish the disadvantages for future ADCs.

References

1. Thery JC, Spano JP, Azria D, Raymond E, Penault Llorca F. Resistance to human epidermal growth factor receptor type 2-targeted  therapies. Eur J Cancer. 2014 Mar;50(5):892-901.