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Evolution of Antibody-Drug Manufacturing

Antibody-drug Conjugates (ADCs) have evolved since the initial approval of gemtuzumab ozogamicin (Mylotarg®) in 2000, with respect to conjugation, linker and toxin chemistries and processing. With the current availability of 4 commercially approved drugs and approximately 80 programs in various clinical trials, there has been a significant interest in simplifying the complex supply chain.

With approximately 80% of the programs outsourced to Contract Development and Manufacturing Organizations (CDMOs), a transparent and integrated supply chain is critical for the success of ADC projects.

This white paper will describe how chemistry and manufacturing have evolved over the past 10 years globally and how MilliporeSigma, as a CDMO, has adapted to these changes to meet customer’s needs.

Register to download this free white paper

Learn more about:

  • how ADC manufacturing has evolved over the past decade
  • the challenges that this evolution implies
  • why the success of ADC projects are increasing tied to an integrated supply chain

Last Editorial Review: October 1, 2018

Featured Image: Scientist at MilliporeSigma Courtesy: © 2017 – 2018. Fotolia Used with permission.

Copyright © 2017 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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Lonza Expands Manufacturing Capacity for ADC Payloads

Lonza, a specialty contract development and manufacturing (CDMO) partner to the biopharma industry, will add new highly potent API (HPAPI) manufacturing suites at its site in Visp, Switzerland. The expanded capacity is for the specific support of antibody-drug conjugate (ADC) payload manufacturing.

By leveraging the company’s more than 100-year experience in chemistry, biopharmaceuticals and small molecule drug process development and scale-up, Lonza as developed a reputation in manufacturing and support of both clinical development and commercial licensing of antibody-drug conjugates (ADCs).

The expansion is based on a tailored business agreement with a major biopharmaceutical partner that ensures ADC payload supply continuity and flexibility at reduced cost of goods

This latest expansion includes two new manufacturing suites. These new suites enable handling of a variety of highly potent products with occupational exposure levels down to 1ng/m3 and strengthen the overall bioconjugation capabilities of the company.

Strategic decision
The expansion underlines the strategic position of antibody-drug conjugates in the Lonza Pharma & Biotech portfolio, with the company developing and producing all components of this increasingly important cancer treatment: cytotoxic payloads, antibodies and the required linkers.

The first of the two new HPAPI suites specifically supports a global biopharmaceutical partner by securing the long-term supply of highly potent ADC payloads.

The second suite will be available to other customers for similar HPAPI and payload development and manufacturing programs. The expansion also increases Lonza’s capabilities in providing fully scalable HPAPI and ADC solutions from lab to commercialization, which supports the accelerated timelines that many drug programs in this category require.

“By ensuring critical supply for the treatment of cancer patients, we are supporting one of our global partners in the oncology field,” said Maurits Janssen, Head of Commercial Development of the API Business Unit at Lonza Pharma & Biotech.

“Oncology continues to be the leading indication in biopharma and the main driver for bioconjugates. We continue to increase capabilities and capacity to meet the HPAPI development and manufacturing needs of our partners,” Janssen added.

Partner
Lonza is an established partner in developing and manufacturing HPAPI, with more than 20 years’ experience in safely progressing more than 30 products from early-stage work to late-stage clinical or commercialization. The company has the capabilities in place to safely handle HPAPIs to exposure levels down to 100ng/m3 across all manufacturing scales. These new suites will extend the options for companies developing APIs with even higher potencies.

“Our customers developing highly potent medicines need a partner whom they can trust to handle these toxic substances and to deliver in sync with their needs, whether for clinical or commercial supply,” said Gordon Bates, President Chemical Division at Lonza Pharma & Biotech.

“Combined with our expertise in biologics development, manufacturing, bioconjugation and sterile fill/finish, this new capability will offer further solutions for companies developing complex therapies,” Bates concluded.

Future of ADCs
The expansion confirms Lonza’s belief in the growing global therapeutic potential of ADCs which is, according to experts expected to grow to US $ 4bn by 2023, with double digit approvals within 3-years.

As part of this growth, novel payloads that target tumor-initiating cells on third generation antibody-drug conjugates or ADCs could come to market in the next couple of years. Driven by a healthy late stage pipeline, experts confirm that they expect the market for antibody-drug conjugates to expand at around 19% compounded annual growth rate (CAGR) between 2017 and 2030.[1]

These predictions are based on a new analysis published in the 2018 edition of the CPhI Annual Report – the complete findings of which were released earlier this month at CPhI Worldwide in Madrid, Spain, the global pharmaceutical event held October 9 – 11, 2018.[1]

Lonza’s HPAPI and ADC payload expansion, which is, in part, based on these expectations, is expected to be on-line by the end of 2019.


Disclosure: Lonza is one of the underwriting sponsors of ADC Review | Journal of Antibody-drug Conjugates.

Last Editorial Review: October 26, 2018

Featured Image: Lonza, Visp, Switzerland. Courtesy: © 2010 – 2018 Lonza, Visp, Switzerland. Used with permission.

Copyright © 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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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.

Creative Commons License

This work is published by InPress Media Group, LLC (ADCs – Look Forward to a Potent Future) and is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. Non-commercial uses of the work are permitted without any further permission from InPress Media Group, LLC, provided the work is properly attributed. Permissions beyond the scope of this license may be available at adcreview.com/about-us/permission.


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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ADCs – The Dawn of a New Era?

The technology behind antibody-drug conjugates (ADCs) has been around for many years, but so far is without widespread commercial success. Penelope Drake and David Rabuka of Catalent Biologics assess the history and progress to date, and look at what might be preventing ADCs from reaching their full potential.


Abstract
Two decades ago, antibody-drug conjugates or ADCs were hailed as a major breakthrough, especially in the area of oncology therapeutics. The concept of delivering a potent drug payload directly to the site of the tumor for maximum effect with minimal damage caused to non-cancerous cells was viewed as, if not the Holy Grail of cancer treatment, at least a significant advance towards precision medicine. However, the concept has proved difficult to translate into clinical success.

1.0: Introduction
The first ADC reached the market in 2000, but to date, the U.S. Food and drug Administration (FDA) has approved only four ADC therapeutics. The two most recent were granted approval in 2017, and could mark the start of a new era in which ADCs begin to realize their full potential.

The two drugs approved most recently by the FDA are inotuzumab ozogamicin (Besponsa®) and gemtuzumab ozogamicin (Mylotarg®). Mylotarg, the very first marketed ADC, was originally approved in 2000 for treatment of CD33-positive acute myeloid leukemia (AML).

However, treatment-related toxicity concerns led to its withdrawal from the market in 2010, but it has now been re-approved with a lower recommended dose and altered dosing schedule.

Besponsa was approved for treatment of relapsed/refractory acute lymphoblastic leukemia (ALL).[1,2] They join brentuximab vedotin (Adcetris®), an anti-CD30 monomethyl auristatin E (MMAE) conjugate approved in 2011 to treat relapsed/refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, and ado-trastuzumab emtansine (Kadcyla®), an anti-HER2 DM1 conjugate approved in 2013 to treat HER2+ metastatic breast cancer. Kadcyla is currently the only FDA-approved ADC for the treatment of solid tumors.

2.0: An Hybrid Entity
An ADC is very much a hybrid entity, combining both biologic and small molecule characteristics, and consisting of an antibody scaffold covalently modified with a variable number of small-molecule payloads, joined by a chemical linker. The antibody delivers the small molecule specifically to the intended cell type by targeting an antigen that is selectively expressed on tumor cells and internalizes upon antibody engagement. To be an effective therapy, all of these parts of the ADC must be optimized.

Changes to the linker can have a significant effect on the biophysical and functional performance of the ADC, and there are two main conjugation approaches for attaching linkers to antibodies, resulting in either heterogeneous or site-specific payload placement. Currently, the ADC clinical pipeline is still dominated by heterogeneous conjugates, although the functional and analytical advantages of site-specific conjugation [3] are now being recognized.

The average ratio of conjugated payload to antibody is referred to as the drug-to-antibody ratio (DAR) and this has a strong influence on both the efficacy and toxicity of an ADC. High-DAR ADCs can have poor biophysical characteristics that reduce efficacy and increase toxicity, but these effects can be mitigated using certain conjugation and linker technologies.[3]

3.0 Clinically-tested Payloads
To date, the majority of clinically-tested ADC payloads are either antimitotic/microtubule inhibiting, such as auristatins, maytansinoids and tubulysin, or DNA alkylating (e.g., pyrrolobenzodiazepines, indolinobenzodiazepines, calicheamicins, duocarmycins), although a few other interesting payloads with novel mechanisms of action have been introduced (irinotecan derivatives and α-amanitin).

The past five years however, have seen a dramatic change in the ADC clinical pipeline as preclinical technological advances have started to feed into clinical-stage projects. In early 2013, of the 20 ADCs in the clinic, nearly 80% were heterogeneous conjugates with payloads of antimitotic drugs, namely auristatins or maytansinoids. But between 2013 and 2017, the number of ADCs in clinical trials more than tripled [4], with site-specific ADCs accounting for nearly 15% of the total. There has also been a trend away from antimitotic payloads towards more potent cytotoxic drugs, particularly DNA alkylators.

The proportion of antimitotic payloads fell from 80% to 65% overall, and accounted for only one-third of site-specific ADCs. This decline can be attributed in part to the unimpressive clinical results of ADCs bearing antimitotic payloads.

According to a recent review [4], nearly 40% of ADCs bearing maytansine, monomethyl auristatin E (MMAE), or monomethyl auristatin F (MMAF) that entered clinical trials were later discontinued, presumably due to lack of efficacy or (rarely) excessive toxicity.

However, the highly potent DNA alkylating payloads carry an increased risk to patients and the fine line between potency and safety is one that scientists and regulators are still striving to achieve. The first site-specific ADC to reach the clinic, vadastuximab talirine, is an anti-CD33 antibody conjugated through engineered cysteine residues in the heavy chain to yield a DAR 2 molecule and is the first clinical ADC to bear a pyrrolobenzodiazepine (PBD) payload, a highly potent DNA alkylator.

It began clinical phase 1 trials in mid-2013, but the phase 3 trial was recently terminated due to toxicity concerns[5], even though the drug showed a 70% complete remission rate for AML patients.[6]

4.0: Mechanisms of toxicity
Meaningful improvements in ADC technology are expected to continue as preclinical studies focus on understanding the mechanisms of ADC toxicity, developing approaches for reducing off-target toxicities, and improving patient outcomes through changes in both ADC composition and clinical trial study design.

As yet, most clinical experience has been with ADCs carrying antimitotic payloads, which show prominent organ toxicities in the hematopoietic compartments and in the liver. Much less is known about the clinical effects of dosing DNA alkylators, although targeting of the hematopoietic compartments has been shown in clinical trials.

A deeper understanding is needed of the absorption, distribution, metabolism, and excretion (ADME) and drug metabolism and pharmacokinetics (DMPK) fates of both the intact conjugate and its small molecule component. Knowing where the drug goes and how it is processed will enable connections to be drawn with commonly observed clinical toxicities.

A 2015 review of toxicity studies [7] concluded that ADC toxicity was not driven by target antigen but rather by linker/payload: ADCs sharing the same linker/payload composition tended to reach the same maximum tolerated dose, even when their target antigens showed endogenous expression in completely different tissue/organ compartments.

This sobering observation revealed how much progress still needs to be made to achieve specific cytotoxic payload delivery to tumor cells without damaging healthy tissues. But it also offers a possible explanation for the high failure rate of 2013 era ADCs.

It is likely that the lack of clinical benefit observed for some ADCs was the result of an inability to dose to an efficacious level due to off-target toxicities driven by the linker/payload.

If ADC off-target toxicity can be controlled, then it is likely that the maximum tolerated dose can be increased, perhaps leading to better clinical response to treatment.


How to cite:
Drake P, Rabuka D, ADCs – The Dawn of a New Era? (2018),
DOI: 10.14229/jadc.2018.08.27.001.


Original manuscript received: July 25, 2018 | Manuscript accepted for Publication: August 21, 2018 | Published online August 27, 2018 | DOI: 10.14229/jadc.2018.08.27.001.

Last Editorial Review: August 25, 2018

Featured Image: Medical research | Microscope. Courtesy: © Fotolia. Used with permission.

Creative Commons License

This work is published by InPress Media Group, LLC (ADCs – The Dawn of a New Era?) and is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. Non-commercial uses of the work are permitted without any further permission from InPress Media Group, LLC, provided the work is properly attributed. Permissions beyond the scope of this license may be available at adcreview.com/about-us/permission.


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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New Reports Suggests Antibody-drug Conjugates Market to Set Phenomenal Growth in Key Regions by 2023

A new market research report published in late June by HTF market Intelligence Consulting, suggests that the Antibody-drug conjugates (ADC) Market in China is expected to grow exponentially.

The study forecast growth to 2022 and presents an in-depth strategic assessment of the antibody-drug conjugates, highlighting a number of influencing factors impacting or reinforcing market environment, including government policy, technological changes along with market drivers.

Growing footprint
One of the key markets covered by the authors of the report is China and highlights the growth in China, the increased, and growing, manufacturing base and geographic footprint. Finally, the report strategically profiles key players in the market and comprehensively analyze their growth strategies.

With a population of 1.4 billion [*] and a rapidly expanding economy, China has become a manufacturing powerhouse. In addition, China is pursuing a goal of becoming a major hub for international bio-pharmaceutical product research, development and manufacturing. In realizing the first steps in this ambitious goal, China has, over the past decade, become a major destination for the global pharmaceutical industry to conduct R&D activities.[1]

The study, which entirely focuses on antibody-drug conjugates, considers key data such as (current) revenue, market size, expected growth, and price from all major biotechnology and pharmaceutical companies operating in China.


[*] 2017

Last Editorial Review: July 4, 2018

Featured Image: Life scientists Business.  Courtesy: © 2010 – 2018. © Fotolia. Used with permission.

Copyright © 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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A New Maytansinoid-Payload for Antibody-drug Conjugates Development

Established in 2004, Creative Biolabs, a highly specialized company in advanced antibody biochemistry and engineering, released a novel, high-quality, maytansinoid-payload for the development of antibody-drug conjugates

With years of experience and based on the company’s advanced DrugLnk synthetic chemistry platform, Creative Biolabs has created a comprehensive offering for antibody-drug conjugates (ADCs) developments.

As members of the ansamycins superfamily, maytansine and the chemical derivatives of maytansine, called maytansinoid, contains 19-member macrocyclic lactams attached to a chlorinated benzene. Originally isolated from an Ethiopian shrub Maytenus ovatus, maytansine exerts extremely high anti-mitotic potency.

Maytansinoids are microtubule-targeting agents that share same binding site with vinca and function by depolymerizing microtubules and arresting cells in the mitosis stage. The cytotoxicity of these agents is more than a 100-fold higher than vinca alkaloids, making them suitable candidates in anti-cancer therapies utilizing tissue-specific drug delivery strategies, such as antibody-drug conjugates.

Maytansinoids exert cytotoxicity against a number of tumor cell lines and inhibit tumor growth in vivo. In human clinical trials, maytansine have showed a small therapeutic window due to its neurotoxicity and harmful effects on the gastrointestinal tract.


Figure 1.0: Chemical structures of maytansine and its derivatives. Both DM1 and DM4 have been used as payloads for ADC development

However, antibody-drug conjugate or ADC  significantly increase the therapeutic window of maytansinoids comparing to the free drugs, enabling the usage of an otherwise highly toxic drug in cancer treatments.

Linkers
Linkers accommodate different conjugation chemistries on both antibodies and payload drugs. They are an important portion in an ADC because they not only contribute to the stability of the complex in systematic circulation but also dictate the payload release mechanisms once internalized and trafficked into designated cellular locations. We commonly categorize linkers based on their release mechanisms into cleavable linkers (peptide linkers, β-glucuronide linkers, pH-sensitive linkers, and Glutathione-sensitivity linkers) and non-cleavable linkers.

Antibody-drug Conjugates
As tubulin inhibitors, maytansinoids and its analogues inhibit the assembly of microtubules by binding to tubulin at or near the vinblastine-binding site.

Maytansinoid can decrease microtubule dynamic instability and cause mitotic arrest in cells, similar to the MOA of vinblastine. We can provide several antibody-maytansinoid conjugates as good anti-cancer candidates, such as T-DM1 (trastuzumab-MCC-DM1).

It is an ADC in which maytansinoid is conjugated to the anti-HER2 antibody trastuzumab showed superb efficacy against metastatic breast cancer. Meanwhile, lorvotuzumab mertansine (huN901-SPP-DM1), a CD-56 targeting ADC, has also revealed hopeful results in solid and liquid tumors that express CD56.


Last Editorial Review: June 24, 2018

Featured Image: Life scientists researching in laboratory. Focused female life science.  Courtesy: © 2010 – 2018. © Fotolia. Used with permission. Figure 1.0: Chemical structures of maytansine and its derivatives. Both DM1 and DM4 have been used as payloads for ADC development. Courtesy: © 2010 – 2018. © Creative BioLabs . Used with permission.

Copyright © 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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Are Small-Format Drug Conjugates a Viable ADC Alternative Solid Tumors?

Antibody-drug conjugates or ADCs are complex immunoconjugates. They are designed to selectively deliver a small-molecules cytotoxic payload to cancer cells. Directed to specific tumor antigens, antibody-drug conjugates consist of a monoclonal antibody linked via a molecular linker to a cytotoxic agent. [1]

In addition to the targeting monoclonal antibody, the linker technology is crucial. The linker needs to be sufficiently stable in circulation to allow the payload to remain attached to the antibody while, at the same time should allow efficient release of an active cell-killing agent after the antibody-drug conjugate is internalized.

After binding to a specific antigen on the surface of cancer cells, the ADC is internalized where, inside the cell, the cytotoxic payload is released to kill the malignant cell. Today, these cytotoxic payloads include two microtubule-disrupting agents maytansinoids and auristatins as well as a DNA-targeting antibiotic, calicheamicin.[2]

These payloads are included in a number of antibody-drug conjugates approved by the U.S. Food and Drug Administration (FDA). These agents include brentuximab vedotin (Adcetris®; Seattle Genetics) for Hodgkin and anaplastic large cell lymphoma, ado-trastuzumab emtansine (Kadcyla®, also known as T-DM1; Genentech/Roche) for HER2-positive metastatic breast cancer, gemtuzumab ozogamicin (Mylotarg®; Pfizer) for acute myeloid leukemia and inotuzumab ozogamicin (Besponsa®; Pfizer) for the treatment of acute lymphoblastic leukemia.

In addition, nearly 180 other agents are in development – from early stage discovery to advanced stages of clinical development. These novel agents including sacituzumab govitecan for breast cancer, mirvetuximab soravtansine for ovarian cancer, rovalpituzumab tesirine (Rova-T) for lung cancer, depatuxizumab mafodotin for glioblastoma, and oportuzumab monatox for bladder cancer.

While today four antibody-drug conjugates are successfully implemented in clinical strategies, the majority of these ADC are used in liquid, hematological, cancers. The number of antibody-drug conjugates in the treatment of solid, non-hematological, tumor is limited. Most ADCs focusing on solid tumors have not progressed beyond Phase I clinical trials, suggesting that there is an unmet need to optimize additional factors governing translational success.[3]

The first approved antibody-drug conjugates were approved for the treatment of hematologic malignancies. Gemtuzumab ozogamicin is an anti-CD33 antibody conjugated via an acid–labile linkage to calicheamicin. The second approved antibody, brentuximab vedotin, included an anti-CD30 antibody conjugated via a cleavable valine-citrulline (vc) dipeptide linker to the microtubule-disrupting agent monomethyl auristatin E (MMAE).

The first antibody-drug conjugate to be approved for the treatment of non- hematologic, solid tumors was ado-trastuzumab emtansine. This antibody-drug conjugate was developed by conjugating the sulfhydryl group of maytansinoid DM1 to lysine amino groups of the anti-human epidermal growth factor receptor 2 (HER2) antibody, trastuzumab, via reaction with the bifunctional non-cleavable linker, succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC).

While antibody-drug conjugates have been successfully included in therapeutic strategies for the treatment of patients with various forms of malignancies, there is a growing number of agents for which clinical development programs have been discontinued because of insufficient activity at the maximum doses that can be tolerated upon repeat administration. This is especially the case in solid, non-hematological, tumors.

Alternatived to current technologies
Current antibody-drug conjugate-technologies focus on large, whole immunoglobulin formats. Many of these ADCs have been developed with site-specifically conjugated payloads with a DAR (drug to antibody ratio) of 2 or 4.

As discussed above, the majority of ADCs have not had much success in the treatment of solid, non-hematological, tumors.  As result, leading researchers are now exploring alternatives, smaller formats-drug conjugates, including single domain antibody fragment–drug conjugates, single-chain formats such as the scFv, diabodies (head-to-tail dimer of a scFv) and small immuno-proteins (SIPs-scFvs dimerised using a CHε4-domain, approximately half the size of an monoclonal antibody), from 80 kDa to around 1 kDa in total size, which have better penetrating properties as well as more rapid pharmacokinetics (PK).

Discussed in a review by Mahendra P. Deonarain, Gokhan Yahioglu and colleagues, working for Antikor Biopharma, in Stevenage Herts, United Kingdom, and the UK Department of Chemistry, Imperial College London, London, United Kingdom, published in the June 2018 edition of Antibodies (Volume 7, Issue 2), both practical studies and theoretical reviews support the idea that smaller antibody fragments may have faster diffusion and extravasation coefficients and penetrate tumors more rapidly than monoclonal antibodies.[4]

In general, these alternative agents are potent in vitro, particularly the more recent ones incorporating  auristatins or maytansinoids. However, due to the more rapid clearance, the potency profile of these smaller compounds changes when being tested  in vivo. Strategies to manipulate the PK properties, while, at the same time, retaining the more effective tumor penetrating properties, may, as being discussed by Deonarain and colleagues, make small-format drug conjugates viable alternative therapeutics to the more established antibody-drug conjugates.


Last Editorial Review: July 22, 2018

Featured Image: Laboratory Glass works. Courtesy: © 2010 – 2018. Fotolia Used with permission. F

Copyright © 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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WuXi Biologics Starts Construction of a State-of-the-Art R&D and Manufacturing Center – Expands Worldwide

WuXi Biologics, a Hong Kong-listed, open-access biologics technology platform company offering end-to-end solutions for biologics discovery, development and manufacturing, has started the construction of a state-of-the-art integrated biologics conjugate solution center in Wuxi, a city near Shanghai in eastern province of Jiangsu, on the banks of Taihu, one of China’s largest freshwater lakes.

This $20 million 6,000 square meter facility will be operational in 2019 and provide integrated solutions from concept to commercialization for biologics conjugates including Antibody-Drug Conjugates (ADCs) and other protein conjugates.

Antibody-drug Conjugates
Antibody-drug Conjugates or ADCs are complex molecules composed of an antibody linked to a biologically active cytotoxic agent. Over the last decades these drug, 4 of which have been approved by the U.S. Food and Drug Administration (FDA), have emerged as targeted treatments for patients with various forms of cancer.

Building plans
WuXi Biologics plans to build this site into a world-class antibody-drug conjugate research and development and manufacturing platform which will meet cGMP standards from the United States, Europe and China.

“I am very excited about this new investment in ADCs,” Dr. Chris Zhisheng Chen, Chief Executive Officer of WuXi Biologics noted.

“In collaboration with chemistry division of WuXi AppTec Group, WuXi Biologics is one of the few global companies that can provide the one-stop service to global partners for antibodies, small molecule payloads, ADCs drug substance and drug products,” he added.

“Our vision is to empower any global partners to develop any ADC to benefit patients,” Chen observed.

United States Expansion
Earlier this month, WuXi Biologics announced that it is to invest $60 million and hire approximately 150 employees to establish a state-of-the-art biologics clinical and commercial manufacturing facility in Worcester, Massachusetts in the United States.

Supported by the Government of Massachusetts, the Worcester Business Development Corporation (WBDC) and the Massachusetts Life Sciences Center (MLSC), this facility will be WuXi Biologics‘ 11th global drug substance manufacturing facility, the company’s first overseas site in the United States, as well as the third outside China subsequent to Ireland and Singapore.

“Metropolitan Boston is acknowledged as a leader in the biopharmaceutical industry. The new site plays a key role in WuXi Biologics’ global bio-manufacturing network to ensure that biologics are manufactured at the highest quality and within a robust supply chain to benefit patients worldwide. We are grateful for all the support local agencies and the talented people here have provided for us. We believe we can quickly push forward this exciting project,” explained Ge Li, Ph.D, Chairman of WuXi Biologics.

“The new site will undoubtedly meet WuXi Biologics’ growing need for biologics development and manufacturing in the near future. Many partners of WuXi Biologics are located within two hours of this new site,” Chen added.

“We are all very excited to initiate our first US site to enable local companies and expedite biologics development in the United States. We are committed to becoming the most comprehensive capability and technology platform in the global biologics industry to enable both local and global partners,” he concluded.

European Expansion
In April 2018 WuXi Biologics also confirmed that it is to build a €325 million biologics development and manufacuturing plant in Dundalk, County Louth, Ireland. The city is located on the Castletown River, which flows into Dundalk Bay, and is near the border with Northern Ireland, halfway between Dublin and Belfast. The new facility will be built on a green field site at Mullagharlin.

The investment is expected to create 400 permanent jobs and 700 temporary construction positions.

This state-of-the-art facility of the future will be based on the novel approach WuXi Biologics has pioneered deploying multiple single-use bioreactors for commercial biomanufacturing. The facility is also designed to be able to run continuous bioprocessing, a next generation manufacturing technology to be first implemented globally in this 26-hectare campus, the company’s first site outside of China, which is supported by the Irish Government through IDA Ireland.

A total of 48,000 L fed-batch and 6,000 L perfusion bioreactor capacity will be installed, representing the world’s largest facility using single-use bioreactors.


Last Editorial Review: June 19, 2018

Featured Image: Architect and supervisor on building site Courtesy: © 2010 – 2018. © Fotolia. Used with permission.

Copyright © 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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AbbVie Halts SC-007 Development Program in Gastric Cancer

AbbVie has terminated a Phase I clinical trial (NCT03253185) designed to evaluate SC-007, an antibody-drug conjugate  or ADC for the treatment of patients with colorectal or gastric cancer.

The early-stage clinical trial of SC-007, an investigational drug acquired in its takeover of Stemcentrx in 2016 did,  based on interim reports, the multicenter, open-label, Phase I study in patients with colorectal cancer (CRC) or gastric cancer to study the safety and tolerability, not meet but the primary endpoint due to dose-limiting toxicities.

The 2016 acquisition of Stemcentrx was considered one of the largest biotech acquisitions in recent memory. It was also one of the five biggest sales ever of a venture capital-backed company.

Clinical trial
The trial, which stared at the end of September 2017, consisted of a Part A (dose regimen finding) in participants with CRC followed by Part A in participants with gastric cancer. Then, a Part B (dose expansion) was expected enroll participants into separate disease specific cohorts of CRC or gastric cancer.

Being an antibody-drug conjugate, SC-007 will, upon intravenous administration, binds to the tumor-associated antigen expressed on tumor cells. Upon binding and internalization, the cytotoxic agent is released and kills the TAA-expressing cancer cells.

The announcement of failure of SC-007 comes less than a week after another ADC developer, ADC Therapeutics, abandoned their HER2-targeting antibody-drug conjugates ADCT-502.  ADC Therapeutics halted their development program after it became clear in their phase I trial of ADCT-502 would have not  a therapeutic effects without major tolerability concerns.


Last Editorial Review: May 1, 2018

Featured Image: Colorectal cancer. Courtesy: © 2018. Fotolia. Used with permission.

Copyright © 2017 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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ADC Therapeutics Ends ADCT-502 Development Program

Earlier this week Lausanne, Switzerland-based ADC Therapeutics, an oncology drug discovery and development company specializing in the development of proprietary antibody-drug conjugates or ADCs designed to target major hematological malignancies and solid tumors, confirmed that the company has terminated its Phase I clinical trial program for ADCT-502 in patients with advanced solid tumors with HER2 expression.[1]

ADCs are highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with a novel class of highly potent cytotoxic agents linked via a chemical linker.

Figure 1.0: Study evaluates ADCT-502 in patients with Advanced Solid Tumors with HER2 Expression. Patients will participate in a dose-escalation phase (Part 1) and dose expansion (Part 2). In Part 2, patients will receive the dose level identified in Part 1. This is the first clinical study with ADCT-502 in patients with Advanced Solid Tumors with HER2 Expression.

The investigational agent, targeting HER2 expressing solid tumors, did, based on data on safety, tolerability, pharmacokinetics and efficacy, not demonstrate sufficient patient benefit to justify further development.

While the single group assessment trial was planned to have two parts, the expected risk/benefit ratio had not been achieved by the end of part one.

In total, the study enrolled not more than 20 patients (278 were planned) with solid cancers, including breast cancer, non-small cell lung cancer, gastroesophageal, and bladder cancer.

In the first part of the trial, researchers tested the safety and tolerability of ascending ADCT-502 doses. Unfortunately, the initial results showed that anti-cancer responses were only seen at higher doses. These higher doses were not well-tolerated by patients. As a result, the trial failed to achieve its primary objective and was suspended.

PBD-based ADC programs
“We are very pleased with the efficacy and tolerability achieved with our lead hematological PBD-based ADC programs, but regrettably this has not been the case with our HER2 targeted ADC,” said Jay Feingold, Chief Medical Officer and Senior Vice President of Clinical Development at ADC Therapeutics,

Pyrrolobenzodiazepine dimers or PBD’s are extremely potent and have a well characterized safety profile that includes fluid retention and pulmonary edema. For most PBD-based ADCs this can be managed by selecting dosing regimens that are efficacious with manageable toxicities.

“However, during dose escalation in this trial we did not achieve the necessary efficacy at tolerated doses required for patient benefit. This was possibly due to the extensive expression of HER2 in pulmonary tissue,” Feingold explained.

Photo 1.0: ADC Therapeutic at the 2017 annual meeting of the American Society of Hematology in Atlanta, GA.

“Our next two solid tumor ADCs progressing into the clinic over the next nine months incorporate site specific conjugation technology which based on pre-clinical models has the potential to substantially improve tolerability and efficacy in difficult to treat solid tumors. Preclinical data on these programs was presented at the recent American Association of Cancer Research conference,” he added.

“Patients with HER2 expressing tumors have multiple therapeutic options including novel therapies in clinical development that are producing encouraging data. ADC Therapeutic’s strategy is to progress a deep pipeline of ADCs into Phase I in order to assess their clinical and market potential based on actual human data, and only to progress into later stage development those ADCs that demonstrate the potential to be best in class in areas of high unmet medical need.We currently have three other ADC programs in the clinic, and we plan to commence clinical trials for three additional programs in the next 9 months, including a third hematological program,” Chris Martin, CEO at ADC Therapeutics said.

“Moreover, our two most advanced clinical programs are progressing into later stage development over 2018,” he added,

At this time, ADC Therapeutics is collecting and evaluating the study data from the ADCT-502 Phase I-trial, which will be presented for publication later this year.


Last Editorial Review: April 26, 2018

Featured Image: Clinical research Courtesy: © 2018. Fotolia. Used with permission. Photo 1.0: ADC Therapeutic at the 2017 annual meeting of the American Society of Hematology in Atlanta, GA. Courtesy: © 2018. Sunvalley Communication / Evan Wendt. Used with permission.

Copyright © 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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