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PEER-REVIEWED ARTICLES

Developing the Next Generation of Clinically Successful Antibody-drug Conjugates

Since the approval of the first antibody-drug conjugate or ADC, now more than 15 years ago, scientists and researchers have sent more than 50 ADCs to be clinically evaluated in ongoing clinical research programs. While some of the trial results have indeed been impressive, some of the results have been mixed. At a time when some may worry about a high rate of attrition, researchers have correctly pointed out that a high rate of attrition in phase I and II means that only the best trial drugs advance to phase III trials and beyond.

In reviewing the cause of failure of antibody-drug conjugates in clinical trials, researchers are looking at a great number of reasons, including the possibility of linker instability as one possible aspect causing systemic toxicity. But they are also asking if failure may be caused by safety concerns with maximum tolerable dose and low therapeutic index. Why does preclinical data not translate to clinical efficacy in human? Are these problems caused by an insufficient understanding of antibody-drug conjugate metabolism in vivo?

Berlin
This year, from February 8 – 10, 2016, Hanson Wade’s World ADC Summit will be in Berlin, Germany, where leading Experts and Key Opinion Leaders from academia and companies, including Seattle Genetics, Genentech/Roche, Pfizer, MedImmune, Immunomedics and others, will present new antibody-drug conjugates research, insights and updates.  During this meeting, researchers and scientists are expected to share their latest understanding and, above all, lessons learned from preclinical and clinical studies to see how this may help in the development of the next-generation antibody-drug conjugates, and move the industry forward in the right direction.

From discovery to clinic
Over a 3 day period and with more than 60 sessions the World ADC Summit is expected to cover every aspect of antibody-drug conjugate development from discovery, preclinical, clinical and market development. Furthermore, the latest advancements making the development of  the next generation therapeutically successful antibody-drug conjugates will be presented.

The meeting is expected to cover how Seattle Genetics is developing high-DAR ADCs with superior in vivo performance using innovative linker designs. Other sessions will discuss how to enhance chances of successful regulatory approval by hearing views from the U.S. Food and Drug Administration (FDA), how to effectively scale up from clinical to commercial manufacturing and how to create and maintain a robust antibody-drug conjugate manufacturing CMO network.

During the meeting, researchers are also expected to discuss the successful develop of payloads with different mechanisms of action and specific lesson learned from the synthesis and development of novel pyrrolobenzodiazepine (PBD) dimers as potent anticancer agents with a broad spectrum anti-tumour activity in vivo.

Other topics to be discussed include how to overcome serum stability issues associated with thiol linked antibody drug conjugates using N-alkyl maleimides from MedImmune, how to identify novel antibody-drug conjugate targets which have improved internalisation at a higher frequency based on insight from Genmab, improving understanding of IgG limitations and discover validated alternative antibody formats with Roche.

The attendees can also expect to hear from experts from Pierre-Fabre discussing how to improve pharmacokinetic understanding using cutting edge analytical and bioanalytical characterisation approaches, listen to researchers from Bayer talking about maximizing the antibody-drug conjugate drug therapeutic window by learning how to effectively manage off-target toxicities and, finally, get a better understanding of the latest clinical outcomes by reviewing results for Immunomedics‘ clinical phase II trial with IMMU-132 in patients treated for solid cancers who have had multiple prior therapies.


Last Editorial Review: January 25, 2016

Featured Image: Spreepark Berlin is the old East German amusement park flanked by the River Spree, abandoned to the elements on the edge of Berlin’s Treptower Park. The park opened as the VEB Kulturpark Plänterwald for East Germany’s (GDR) 20th birthday in October 4, 1969.  The fall of the Berlin Wall marked the beginning of the end for the Kulturpark. In 1991 the Park was sold to Norbert Witte who opened the park, now renamed as Spreepark, in 1992. Witte put a lot of effort into bringing the park up to Western European standards. However, despite attracting some 1.5 million visitors in 1993, the number of visitors dwindled to only 400,000 visitors in 2001. In November of that year the park finally closed its doors for the last time. Courtesy: © Jan Bommes. Used with permission. This photo is licensed under the Creative Commons Attribution-Share Alike 2.0 Unported license.

Copyright © 2016 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.

A Chemistry Driven Approach to Uniform Antibody-drug Conjugates: New Data on Igenica’s Site-specific Linker Technology Presented at World ADC

Drug companies are aggressively pursuing the development of antibody-drug conjugates or ADCs, powerful three-part bioconjugates comprising a specific antibody targeting molecule, a highly potent cytotoxin payload inhibiting intracellular processes necessary for cell survival, and a linker to connect them. Antibody-drug conjugates are designed to specifically target various forms of cancer, while, at the same time, not harming healthy tissues. However, the current generation of antibody-drug conjugates offers limited benefits to patients because they are heterogeneous drug mixtures containing variants with sub-optimal pharmaceutical properties.

Earlier today, during a plenary session of the 2015 World ADC Summit, being held in the Marriott Marquis & Marina, October 26-29, 2014 in San Diego, California, Randall Halcomb, PhD, Vice President Chemistry at Igenica Biotherapeutics, presented new data utilizing the company’s SNAP site-specific ADC linker technology.

Proprietary technology
The proprietary linker technology addresses major limitations of current and competitive approaches by providing a simple, fast and robust chemically-driven methods for linking a functional, cancer targeting, antibody and small molecule cytotoxic drug to produce antibody-drug conjugates with optimal and uniform ratios of drug to antibody (DAR). The SNAP technology results in a highly flexible bi-functional linker that, by design, yields homogeneous antibody-drug conjugates armed with the optimal toxin payload.

Igenica has successfully applied this technology to synthesize antibody-drug conjugates using multiple antibodies and a variety of payloads.

At the World ADC Summit, Halcomb presented new data comparing the biophysical properties, in vitro potency, in vivo efficacy and pharmacokinetics of ADCs containing Igenica’s SNAP linkers compared to conventional ADCs. The presented findings validated the superiority of SNAP linkers in terms of uniformity, pharmacokinetics, stability and in vivo efficacy as compared to conventional antibody-drug conjugates.

SNAP linkers also enable improved process efficiency, including a fast, robust chemical conjugation and the ability to use traditional antibody production systems, in contrast to ADC approaches that require protein engineering.

Best Scientific Innovations
In addition, Igenica was recognized for its innovative SNAP technology as one of the finalist in the Best Scientific Innovation Category during the World ADC Awards ceremony, being held in conjunction with the World ADC Summit, on Sunday, October 26, 2014. This year, the winner of the category was Spirogen’s (part of AstraZeneca’s MedImmune) proprietary pyrrolobenzodiazepine (PBD) technology which attaches highly potent cytotoxic agents to specific cancer-targeting antibodies using biodegradable linkers. Other finalists in this category included Catalent Pharma Solutions‘ (Redwood Bioscience) SMARTag Technology, CytomX Therapeutics‘ Probodies, and Sutro Biopharma‘s cell free expression system.

“Igenica’s proprietary site-specific SNAP technology represents a breakthrough in ADC uniformity, process efficiency and drug product profile for the next-generation of homogeneous ADCs,” explained Mary Haak-Frendscho, Ph.D., Chief Executive Officer of Igenica. “Our innovative platform has the potential to produce drugs with lower toxicity and higher efficacy, representing an important benefit to cancer patients.”


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