World ADC 2019: Maximizing the Clinical Therapeutic Index of Antibody-drug Conjugates

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With five approved and commercially available antibody-drug conjugates and nearly 100 in various stages of clinical development, it is exciting to see how the idea of a ‘magic bullet,’ envisioned and defined by Paul Ehrlich more than 100 years ago, has become a reality.

As the publisher and executive editor of ADC Review | Journal of Antibody-drug Conjugates, it is truly exciting to see how these unique immunoconjugates have indeed become a real game-changer, changing strategies in the war on cancer.

But cancer is just the beginning.

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A better understanding
Antibody-drug Conjugates result from the bioconjugation of a highly potent cytotoxic anticancer drug connected through linker technologies to a selective antibody, which acts as a ‘targeting’ vector.

While this approach seems ‘simple,’ the realization of these powerful pharmaceutical agents has been fraught with difficulty and failure.

For example, less than 10 year ago in mid 2010, the only marketed ADC at that time, gemtuzumab ozogamicin (Mylotarg®; Pfizer), originally approved in 2000 under the FDA’s accelerated approval program, was withdrawn from U.S. and European markets after it was associated with a serious liver condition called veno-occlusive disease, which can be fatal. In addition, a post marketing clinical trial was discontinued early when researchers did not observe an improvement in clinical benefit in the randomized SWOG 106 study.

Based on these results, Pfizer voluntarily withdrew the drug. However, in September 2017, the FDA (re)approved gemtuzumab ozogamicin with a lower recommended dose, a different schedule in combination with chemotherapy or on its own, and a new patient population.

While the withdrawal of gemtuzumab ozogamicin was seen by many as a major setback, the approval of brentuximab vedotin (Adcetris®; Seattle Genetics/Takeda) in 2011 and (ado-) trastuzumab emtansine (Kadcyla®; Genentech/Roche) in 2013 definitely confirmed the validity of the concept of antibody-drug conjugates while reigniting enthusiasm among scientists, researchers and the investment community.

Today, in addition to brentuximab vedotin, (ado-) trastuzumab emtansine and gemtuzumab ozogamicin, new ADCs have been approved, including inotuzumab ozogamicin (Besponsa®; Pfizer) and polatuzumab vedotin-piiq (Polivy®; Genentech/Roche).

Success is not easy. It involves building on our expanding knowledge of the biology of cancer, getting a better understanding of targeting cancer, the complexity of ADCs and the required science and technology involved, as well as figuring out what went wrong, and discerning underlying problems, when we failed in our development efforts. But it is rewarding – truly exciting – to see how our ‘collective knowledge,’ gained during the development of the currently approved agents and many investigational agents in various stages of clinical development, has resulted in new approaches, new ideas, and new technologies.

Generations of ADCs
With more antibody-drug conjugates moving to late-stage clinical trials, regulatory approval and commercial availability, the development of the next-generation of ADCs is just around the corner. To be effective, these novel, ‘next-gen’ ADCs, conjugating antibody, payload, and linker, will see starkly different sciences and technologies than seen in earlier generations, while, at the same time, ensuring stability, targeted delivery, and limited off-target effects. And while this will lead to better ADCs in oncology and hematology, it will also contribute to ADCs beyond these therapeutic areas.

But what is new? Here are some of the observed new technologies being developed:

  • A new linker antibody-conjugation technology that enables site-specific payload attachment to native antibodies “off-the-shelf” without engineering (i.e. neither the antibody nor the glycosylation needs to be engineered);
  • A novel platform technology of small-format antibody (fragment)-drug conjugates with superior penetrating and clearance properties, and high payload capacity;
  • A novel bioconjugation technology that paves the way for use of novel payloads, showing markedly improved efficacy compared to clinically-validated benchmark ADCs in solid tumor models;
  • A novel drug-conjugate platform consisting of a modular suite of proprietary payloads, linkers and site-specific conjugation technologies designed for the targeted delivery of therapeutics with optimal efficacy and safety profiles.

These developments are truly invigorating. And it’s exciting to see how different generations of antibody-drug conjugates have been developed, each generation with improved structural characteristics, toxicity, and homogeneity.

For example:

  • Gemtuzumab ozogamicin, considered a first-generation antibody-drug conjugate, presented an unstable, cleavable, hydrazone linker. The drug was associated with targeting and instability issues during plasma circulation, leading to a high toxicity profile.
  • Then, (ado-) trastuzumab emtansine, considered a second-generation antibody-drug conjugate, demonstrated significant enhancements. These enhancements included a more stable non-cleavable linker and reduced off-target toxicity, resulting in an improved therapeutic index.
  • And while low therapeutic index is still a problem for most antibody-drug conjugates in development, a third-generation of antibody-drug conjugates, using site-specific conjugation technologies, leading to highly homogeneous drug-to-antibody ratios (DAR 2 or 4), have been produced with very potent cytotoxic payloads, including pyrrolobenzodiazepines (PBDs), tubulysins and pyridinobenzodiazepine (PDDs).

Novel payloads used in the development of antibody-drug conjugates have improved hydrophilicity over more conventional DNA binding agents, facilitating antibody conjugation. The structure of these new payloads, each with different mechanisms of action, uniquely permits a variety of linker attachment sites.

While the development of these novel payloads has challenged synthetic organic chemists, it has also resulted in the development of a library of potential payloads designed to address the medical needs for the treatment people with various types of cancers.

As seen over the last decades, each ‘next generation’ of ADCs employs a variety of novel conjugation platforms, linker chemistries and payloads, each designed to address limitations of earlier generations. While this, know doubt, increases the diversity and complexity of next generation ADCs, it will also present additional challenges.

Although real, what many decades of developing novel ADC has shown us, is that challenges in early discovery, ongoing preclinical and clinical trials have not only enabled scientists to better understand the mechanisms of action of antibody-drug conjugates, they have, each time, invigorated scientists – and created new fields of study aimed at successfully overcoming these challenges.

Manufacturability
The complexity of antibody-drug conjugate is also evident in the challenges of manufacturing.  The generally fragmented supply chain with crucial, logistical challenges, requires essential understanding of, for example, product process and release testing for efficient technology transfer and a clear understanding of how to manage this throughout the development and manufacturing process. It also requires translational skills to guide the development, and ultimately, the successful (commercial) manufacturing of antibody-drug conjugates.

An approach to meet manufacturing challenges should be founded on a symbiotic collaboration between the R&D, analytical and manufacturing teams, while, at the same time, be focused on the quality and manufacturability of bioconjugation and purification steps. And to assure the fit between the developed process and the manufacturing plan, a strong analytical approach is necessary to control the process and the final therapeutic agent.

Beyond cancer
Listening to many experts in the industry, academic centers and research institutes, I strongly belief in the potential of antibody-drug conjugates to become, in the near future, a game-changer in other therapeutic areas as well.

The majority of antibody-drug conjugates are still being developed for the treatment of patients with cancer. But based on what the experts are saying, some ADCs are now also being developed outside the domain of oncology and hematology. These agents, generally focusing on indications in immune modulation and anti-infection, are still limited in number and are mainly in (early) discovery and preclinical stage of development.

According to the experts, one of the key differences between ADCs for oncological indications and non-oncological indications is that payloads for non-oncological indications are designed to modulate biological functions without affecting cell viability. These payloads are generally non-toxin-based and are largely less potent compared to cytotoxic payloads.

Hence, to be effective, ADCs for non-oncological indications require a higher standard in terms of selection of targets, antibodies and linker chemistry, as well as conjugation approaches, to achieve sufficient binding, efficient internalization, and payload release.

While complex, these novel approaches, I belief, will ultimately become reality.

A place to learn
The success seen in the development of antibody-drug conjugates would not have been possible without collaboration, discussions, many informal exchange of ideas between peers. And while there are a number of academic, industry and medical (society) meetings covering many aspects of the development of antibody-drug conjugates as well as offering network opportunities, one meeting stands out.

World ADC, organized by Hanson Wade, to be held in San Diego, CA, October 8 – 11, 2019, is, no doubt, the premier event providing an appropriate platform to engage and discuss new ideas with peers, while, at the same time, facilitating a professional, but pleasant, environment.

Designed to help forward thinking researchers from the pharmaceutical, biotech and academic communities advance the development of antibody-drug conjugates, World ADC has become a must-attend leading conference for the ADC community.

World ADC has been very successful in bringing together people with many skills as well as centers of interest focusing on antibody-drug conjugates and addressing strategies and the latest innovations from initial chemistry to biology, from early, fundamental research and development to commercial manufacturing as well as different institutions in academia, industry, regulators and clinicians.

Celebrating its 10th year, the theme of World ADC 2019 is:  Maximizing the Clinical Therapeutic Index of Antibody-drug Conjugates.

With more than 88 expert speakers, this conference will offer a feast of information, unrivaled learning and many networking options.

This year, World ADC will shed light on how antibody-drug conjugates can be optimized for the future. Expect a 360° view of antibody-drug conjugates from key stakeholders with detailed presentations in over 4 streams, 3 focused seminar days and 9 interactive workshops addressing:

  • Emerging discoveries, cutting-edge knowledge, new tools, methods, technologies to design novel
  • Discovery, development, and bioanalytical strategies
  • Optimizing conjugation chemistry and stability
  • Develop alternative scaffolds and new payloads
  • Improve therapeutic index
  • Accelerating successful translation to the clinic
  • Improve the clinical trial process
  • Enhance the relationship between payload, linker and antibody to clinically increase efficacy
  • Establishing a robust and efficient manufacturing & supply chains
  • Using Drug Metabolism and Pharmacokinetics (DMPK) modelling to mitigate toxicities and allow for smoother translation into the clinic

World ADC Awards
An integrate part of part of World ADC are the World ADC Awards.  These awards showcase the innovation, leadership and devotion shown by the best companies, teams and individuals in the industry. The Awards will recognize the extraordinary endeavors, teamwork and commercial acumen that has propelled the field of antibody-drug conjugates to the forefront of cancer research today.

Expect World ADC San Diego to be packed with content and dedicated interactive formats, so, make sure that you are equipped to fully benefit from this year’s World ADC.

And, just like you, I’ll be excited to review the takeaways of the conference and to see how the many learnings will be used to maximize the clinical therapeutic window of novel ADC candidates.

I’m looking forward to seeing you in San Diego!