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ADCs – Look Forward to a Potent Future

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

Featured Image: Medical research | Test tubes in medical research. Courtesy: © Fotolia. Used with permission.

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Copyright © 2010 – 2018 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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PharmaMar and Seattle Genetics Sign Licensing Agreement for Fully Synthetic Marine-derived Payloads

Earlier this week PharmaMar, an Madrid-based biopharmaceutical company developing innovative marine-derived anticancer drugs, signed an exclusive agreement with Seattle Genetics in which the company licenses proprietary, fully synthetic marine-derived payload ‘molecules’ for the development, manufacture and commercialization of novel antibody-drug conjugates or ADCs.

Under the terms of the agreement PharmaMar receives an upfront payment of US $ 5,000,000.00 followed by development milestones if an antibody-drug conjugate using PharmaMar’s cytotoxic payload enters clinical development. PharmaMar is also eligible for royalties, once a product receives regulatory approval and is commercialized.

As part of the agreement, Seattle Genetics receives exclusive worldwide rights the selected cytotoxic molecules.


... [the agreement] … allows us to work together in [the development] of these cutting-edge cancer treatments…


Marine Payloads
PharmaMar was the first company in the world to develop a marine-based cancer drug from discovery through to commercialization. The proprietary, fully synthetic marine-derived payloads developed by PharmaMar and which are part of the licensing agreement with Seattle Genetics, are new, structurally diverse molecules with novel mechanisms of action that provide a unique opportunity to develop next generation ADCs.

In the development of these cytotoxic payloads, scientists at PharmaMar take inspiration from the sea to discover these novel molecules with highly potent, sub-nanomolar cytotoxic activity.

“We are glad to sign this license agreement with Seattle Genetics, a pioneer and leading company in the ADC market, because it allows us to work together in [the development] of these cutting-edge cancer treatments,” noted Luis Mora, Managing Director of PharmaMar ́s Oncology Business Unit.

Development process
Between 1960 and 1981 the National Cancer Institute (NCI) screened 114,000 extracts of 35,000 plants, mainly collected in temperate regions. The results of this screening confirmed that between 0.4% to 1.8% of natural extracts of natural material (from terrestrial plants to marine animals) may contain anti-cancer activities. [1]

Continuing the discovery and development of novel anti-cancer agents, PharmaMar, today, has the world’s largest collection of marine organisms. This collection contains nearly 200,000 samples of macro- and micro-organisms.

As part of the development of novel marine-derived payloads, researchers at PharmaMar conduct
multi-phase research programs to discover and develop new anti-tumor compounds of marine origin.

The first phase of the process involves gathering samples of marine organisms (mostly
invertebrates). The biological activity of these samples are assessed and further investigated.

Following this phase, substance responsible for anti-cancer activity, are isolated and its chemical structure established. Then, a chemical synthesis process for its industrialization is designed after which the pharmaceutical formula of the new compound is defined.

“In vivo” models are designed to test the efficacy in a range of different tumors. If the results are positive, research continues in pre-clinical and clinical phases. This unique approach has resulted in a portfolio of products that are at various stages of clinical development.


Last Editorial Review: February 14, 2018

Featured Image: Tropical fish with corals and algae in blue water background of the underwater world. Courtesy: © 2010 – 2018 Fotolia. Used with Permission.

Copyright © 2010 – 2018 InPress Media Group, LLC. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Q&A – an Interview with Lonza’s Laurent Ducry

Antibody-drug Conjugates or ADCs are among the most exciting drug developments of the last decade. The combination of potent, small molecule drugs with the highly target specificity of monoclonal antibodies allows sensitive discrimination between healthy and diseased tissue. This approach has demonstrated great efficacy – and safety – in the fight against cancer and hematological malignancies.  Antibody-drug Conjugates are part of a specialized subset of highly potent active pharmaceutical ingredients (APIs).

Today, the development of this technically challenging new class of highly potent biopharmaceutical drugs is rapidly expanding. On average, each month more than one new ADC is entering a clinical trial.  This progress, as well as the increased development of innovative payloads, novel linkers chemistry and new site-specific conjugation technologies, is creating much excitement among scientists and researchers involved in the development of these specialized, personalized and targeted therapeutics.  But, looking ahead, the excitement among researchers and scientists is especially good news for patients  and their physicians who are trying to help find solutions for, so far, unmet medical needs.

This interview is the first in a series with experts involved in the research, development and manufacturing  of Antibody-drug Conjugates. We will be talking to individual scientists and researchers involved in the development process as well as key employees of pharmaceutical companies, contract (development) manufacturing organizations and physicians involved in clinical trials with ADCs.

Earlier this year we interviewed Lonza’s Laurent Ducry, PhD, who, since 2008, is leading the antibody-drug conjugates R&D group of Lonza (Visp, Switzerland).  Ducry is editor of “Antibody-Drug Conjugates: Methods and Protocols” (Springer, Humana Press, 2013) and a member of the Editorial Advisory Board of ADC Review / Journal of Antibody-drug Conjugates.

In this interview we discussed a variety of subjects related to the development of ADCs, how market conditions and the industry are changing, the impact of personalized and targeted therapies as well as expectations of approved drugs, drugs in the growing pipeline of novel ADC and how this is impacting medicine.

Projections
ADC Review (Question): The ADC market is a growing market. What is your expectation for the ADC market in the next 5-10 years? In particular, with 2 currently approved drugs, and more than 40+ in clinical trials (a number that is growing every month), what do projections look like?

Laurent Ducry (Answer): We expect to see significant growth in what we call targeted drugs and bioconjugates/ADCs are certainly within that category. At ASCO this year, we did see some very promising data from ADCs in the clinical pipeline and we definitely expect to see them in the cancer therapy toolbox in the next 5-10 years. Also, the pipeline is expected to grow considerably, which is evidenced by the significant activity we see in both in-house research and licensing activities.

Changing medicine
Question: How is the development of ADCs, and other targeted therapies, such as CAR-T, PD-L1s and nanodrugs, changing medicine? What does this means for the industry?  How does this impact the need for specialized companies like Lonza?

Answer: This is an exciting time for our company. We are the leading CMO in the world with substantial experience in manufacturing targeted therapeutics technologies and bringing them to the market. Cell and viral therapies, monoclonal antibodies, and bioconjugates all fall under our areas of expertise. Companies like ours that are already well positioned to provide development and manufacturing services for these therapies will benefit from these trends.

We are seeing incredible responses to some of the products utilizing these technologies and the markets are responding accordingly. It is truly a remarkable time to be part of this process.

Personalized and targeted therapies
Question: Based on the previous question. In therapeutic areas like oncology and hematology, there is a drive towards personalization/individualization of therapies.  How does this change medicine?  What role, if any, does Lonza play – and, how may this change the role of CDMOs in general. What can Lonza offer to help their (pharmaceutical) clients to be successful in this unique market?

Answer: That is correct, as I mentioned before, targeted/personalized therapies will become the norm especially in indications like oncology and rare diseases. From a manufacturing perspective, each therapy will bring its own challenges but commitment to quality, peace of mind and product launch experience is something Lonza can uniquely offer in this changing landscape.

Impact of novel payloads and improved linker chemistry
Question: Ongoing research points to new developments in ADCs (different linkers, payloads and monoclonal antibodies. How does Lonza expect this to impact the market? And, how does Lonza’s experience benefit industry players.  How is this different from other industry players?

Answer: I think we will start to see more and more of these newer generation products hitting later phases and every new wave should bring differentiating advantages. From a development perspective, you need teams that have enough experience to handle these complex and new technologies. As a leader in the ADC business, we can safely say our research and development teams have seen and have had experience with almost all of the novel technologies and methods we see coming down the pipe. We know not many CMOs can say that confidently.

Shaping the future
Question: How does Lonza see the future or these novel drugs and what is the role Lonza plays in shaping the future of ADC and other targeted therapies?

Answer: When we are dealing with oncology and rare diseases, what we have learned is that one size-fits-all approach can only provide marginal benefit to patients. We will need novel treatments utilizing newer technologies like cell therapy and ADCs and also we will need to employ combination treatment algorithms. Developing and manufacturing these therapies, some of which may be used concomitantly requires combining several specialized teams of scientists working together. We have these teams ready to be deployed as soon as our customers come to us.

A quantum leap
Question: How do those changes impact health policy in the United States and abroad?  How does this impact treatment and treatment “value” and, finally, how does this impact medical technology?

Answer: Targeted and combination treatments will have multiple implications from a policy and value perspective. First of all, companies need to think creatively in terms of identifying those patient groups that will benefit from these novel products and providing access to them. Also, for the first time we are seeing almost a “quantum leap” in terms of the potential benefits of these products. “Cure” is often used to describe the patient responses achieved in early clinical trials. Obviously, this brings the question of “value” and payment methods. Also, how you will manufacture, administer, get paid for these combination therapies is an additional challenge. This is where forming a strategic partnership with a powerful CDMO that can tackle the manufacturing challenges and also assist through the approval and reimbursement processes will be crucial for pharma/biotech companies.

There are only a few facilities/companies around the world capable of offering a “one-stop shop” for the development of ADCs (from monoclonal antibody development/production to linker technology, cytotoxins, fill/finish, regulatory services, etc.). How does Lonza support their clients in this important therapeutic area and how does the company help customers seamlessly scale ADC production from preclinical to commercial phases? Given the announcements and media attention to SAFCs expansion, how important is geography?  How is an U.S, based competitor facility expected to impact Lonza? What is Lonza doing to counter this?

When you look at the landscape of facilities that manufacture ADCs, we see a disparity between companies in terms of strength in different areas. Some have more mab or cytotoxin experience, some are emphasizing fill/finish capabilities, etc. In my opinion, there is only one company that has the amount of experience in every “piece-of-the-ADC-puzzle”. We have had a good number of successful biologic product launches and a strong track record with ADCs.

For some companies, geography may play a role in their decision to pick a CMO but at the end of the day, most of the customers we work with would eventually target the global market. “Would you prefer proximity over expertise?” is an important question to ask when you make a decision.

Question: Can you describe some of the developments and additional services/updates created by Lonza, and how does this set the company apart? What makes Lonza the industry leader in the ADC market? What is new, unique? What has worked and what did not?

Answer: We are investing in our development capabilities and manufacturing facilities on an ongoing basis. Because of our reputation, companies are eager to bring new technologies like different site specific conjugation methods, novel toxins, etc. to us. Therefore, we have amassed a technology know-how among our scientists that is We have seen every site-specific conjugation method, every major toxin-linker combination available in the pipeline. Our facilities are state-of-the-art. We now have single-use systems available for our customers and we constantly look for ways to improve both product efficacy, safety and manufacturing methods.

A competitive field
Question: In a recent conversation with representatives from Merck KgaA, it was made clear that Merck is expanding its offerings in targeted therapies. In 2014 Merck took over SAFCs parent company (Sigma Aldrich).  How important is this development?  How does Lonza view this?  Is there a benefit to be part of large pharmaceutical company or are there more benefits to operate independently (like Lonza is doing today)? How does Lonza feel, will this ‘merger’ change the (CDMO) industry?

Answer: It is an important development and we are watching their strategy closely. The benefit for Merck is obvious, however, we are working in a very competitive field where manufacturing details could set one product apart from another. Having that sensitive information in the hands of an independent company like Lonza vs. the subsidiary of another pharma company is something to think about. We have already heard our customers voice that reluctance.

The ultimate cancer toolbox
Question: What are some other changes (industry and market developments) that will impact the industry and market in the (near) future – 2015 – 2020 – 2025?

Answer: Nano technologies, T-cells, different payloads are all being tested and while it is hard to predict a clear winner, it is clear the pipelines will not be homogeneous and the ultimate cancer toolbox will look very different than what we have today.


Last Editorial Review: December 2, 2015

Photo: Laurent Ducry, PhD, since 2008 leading the ADC R&D group of Lonza (Visp, Switzerland) Courtesy: © Lonza. Used with permission.

Copyright © 2015 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Validating Meditope Biosciences’ Unique SnAP Technology Platform

Data presented in an abstract at the annual meeting of the American Association for Cancer Research (AACR), taking place April 18-22, 2015 in Philadelphia, validates the use of Meditope Biosciences‘ (San Diego, CA) proprietary SnAP (Site-specific novel Antibody Platform) technology for the development of antibody-drug conjugates (ADCs).

Discovered by a team of researchers led by John Williams, PhD, of the Beckman Research Institute at the City of Hope, a National Cancer Institute (NCI) designated Comprehensive Cancer Center, the SnAP technology can be best compared as turning antibodies into Lego®-like pieces that can be combined with other pieces to expand functionality by easily attach and detach (‘snap‘) anything imaginable on (or off) an antibody without the need for chemical conjugation.  This unique, proprietary, site-specific, platform technology has the potential to advance the antibody market by producing an array of new therapeutic and diagnostic products.

Unique technology
The patented SnAP technology is based on the simple discovery that a naturally occurring pocket of space in the Fab region of antibodies can be engineered to accommodate another molecule, typically a small peptide, directly into that space. Because it nestles itself in that pocket of space, such a molecule is called a meditope.

By switching out a few amino acids in that pocket of space in the Fab region, any antibody can be meditope-enabled. Meditope Biosciences’ technology also includes the meditopes or cyclic peptides, designed to fit into that enabled pocket or space and bind the Fab fragment noncovalently outside the paratope in this novel and unique site. Simply said, the meditope acts as linker-piece which is “snapped” like a piece of Lego® into the naturally occurring pocket of space in the Fab region.

Once an antibody is enabled, meditopes of varying affinity can be designed to fit in this space with specificity. This unique property makes it possible to ‘conjugate’ cytotoxic payloads to an antibody in a site-specific and consistent manner.

Because each antibody has two Fab regions, two meditope-enabled sites per antibody can be created. This results in a consistent meditope-to-antibody ratio or MAR of 2:1.

No need for complex chemistry
In addition to its simplicity, the SnAP technology avoids the complex chemistry required in other conjugation processes. Rather, a payload can easily be attached to the meditope-linker, which in turn snaps into its binding site on the meditope-enabled antibody.

The available data further shows that neither the meditope-enablement of the antibody nor the binding of a meditope (with or without a payload) to the meditope-enabled antibody interferes with the antibody’s ability to attach to its target.

Versatility
In the presented research, the scientists looked into peptide modifications to increase meditope’s affinity for a specific antibody, and evaluated the transferability of this approach onto a panel of human antibodies of therapeutic relevance. Their data demonstrated the structures and binding characteristics of a panel of “meditope-enabled” antibodies using the SnAP technology platform and confirmed the versatility of the SnAP technology for conjugation of payloads at a single site on each Fab fragment outside its antigen-binding site. [1]

No interference
Scientists at the company demonstrated the successful transplantation of the meditope binding site to several antibodies. Based on their results, meditope-peptides of different affinities were selected by rational design and fine-tuned according to the requirements of specific application. For ADC development, the data showed that the meditope-peptides are conjugated with cytotoxic payloads (including MMAE and DM-1) and the higher the affinity of the meditope-peptide-drug conjugate for the antibody, the higher the complex’s cytotoxic potential against antigen-positive tumor cells.

These complexes were tested in vitro in a panel of tumor cell lines, to measure and rank the efficacy of the leads in for further development as potential novel oncology therapeutics.

Large number of commercial applications
“We are highly enthusiastic about the data [we’ve presented at the AACR meeting] which point to the many commercial applications that may be possible for our unique SnAP technology, including its potential to develop a powerful new generation of antibody-drug conjugate therapies,” noted Elisabeth Gardiner, Meditope Biosciences’ Chief Scientific Officer and an author of the abstract. “Additionally, the attributes of these ADCs, which use SnAP technology, suggest a less complex, more efficient and predictable manufacturing approach, which can offer significant efficiencies in the drug development process,” she concluded.

Gardiner als noted that the SnAP technology can be applied beyond ADCs, including the development of bi-specific antibodies, in which the meditope-connector piece snaps two different antibodies to each other.  Furthermore, the technology also allows for a simpler development of specific diagnostics, theranostics and research tools.


Photo: Microscope lens with a beam of green light.  Courtesy: Sunvalley Communication, LLC /Fotalia

Last Editorial Review: April 21, 2015
Last Update: May 2, 2015

Copyright © 2015 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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