‘More shots on goal’

Glythera and IONTAS agree on next-generation antibody-drug conjugates

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CAMBRIDGE, U.K. & NEWCASTLE, U.K.—Glythera Ltd., an antibody-drug conjugate (ADC) development company, and IONTAS Ltd., a specialist in services and platform technologies associated with the discovery and optimization of fully human antibody drugs, announced in September a collaboration for the development of ADCs for difficult-to-treat cancers.
As part of the agreement, IONTAS will generate novel, fully human antibodies against specified targets for proof-of-concept studies. Glythera will have an option for exclusive, worldwide rights to resulting antibodies for the development of ADCs alongside its proprietary conjugation platform, PermaLink, and its in-house portfolio of novel toxins.
According to Dr. Neil Butt, chief business officer at IONTAS, and Dr. Ian Evetts, chief business officer for Glythera, “Glythera and IONTAS have not previously worked together, but given the history of the IONTAS team in developing antibody therapies, this collaboration offered major advantages in de-risking Glythera’s development activities. IONTAS were keen to exemplify their platform in the ADC arena, so the collaboration was born. In particular, IONTAS saw the need for companies like Glythera to assess panels of antibodies to identify leads that may be more pertinent to ADC use. Previously, ADCs have been developed from ‘naked’ antibody development candidates which may not be the best starting point.”
“Neil and Dave [Dr. David Simpson, CEO of Glythera] have known each other from the industry for some years and re-connected at a recent partnering meeting,” they continue. “Glythera was searching for market-relevant antibodies from which it could generate antibody-drug conjugates using its proprietary conjugation chemistry, PermaLink, so the tie up with IONTAS and its world-class display technology made perfect sense.”
The two companies will select and optimize multiple undisclosed antibodies for ADC development, with Glythera exercising its option right to exclusively develop and commercialize the resulting antibodies in ADC formats. Glythera will continue to evaluate numerous ultra-potent ADC-relevant toxin classes, including novel and known mechanisms, with an intention to nominate its first clinical ADC candidate by 2019.
“Currently there are around 60 different antibodies in the 90 ADCs currently in the clinical development pipeline, so plenty of choice. However, most of the first- and second-generation ADCs contain therapeutic antibodies rather than those selected for ADC-relevant criteria,” Butt and Evetts point out.
“We have short-listed candidates based on core parameters including antigen expression in cancerous tissues vs. healthy tissues, general expression levels, tumor specificity and the degree of antibody internalization. The conjugation stability afforded by PermaLink permits the use of ultra-potent toxins for ADCs with raised therapeutic indices and higher clinical impact.”
IONTAS will utilize its unique antibody discovery services and bespoke phage display libraries for antibody discovery. Glythera will subsequently generate PermaLink-based ADCs which have been shown to provide a near-100 percent improvement in tolerability when compared with maleimide-based ADCs in in-vivo models, as well as enhanced tumor cell-killing and an overall improvement in tumor response in xenograft models. The inherent stability of PermaLink permits the use of ultra-potent toxins for ADCs with enhanced efficacy and safety.
“Currently, Glythera is working with five toxin classes, all with different mechanisms but capable of potently inducing apoptosis. Our intention is to match toxins and antibodies based on cancer cell kill mechanism and tumor selectivity for the generation of optimized ADCs that will have therapeutic benefit in difficult-to-treat solid tumors such as lung, ovarian, liver, pancreas and those associated with the lower intestinal tract,” Butt and Evetts tell DDNews. “Glythera’s second-wave antibody programs will largely focus on novel antigens to ADC formats—antigens and associated antibodies again being selected according to specific ADC-relevant criteria.
“After demonstrating industry-leading conjugation stability, we have been able to access novel, powerful toxins which we will align with antibody targets that are currently in preclinical/clinical development in the ADC space. However, given the conjugation stability, the potency of new toxin classes and their associated mechanisms of cell kill, we are confident of biosuperiority over those currently in development.”
“From the antibody discovery perspective, using a phage display for discovering leads is beneficial in that we can dial-in specific, relevant properties of the antibody early in discovery (e.g. cross species reactivity, specificity and affinity),” they add. “This allows us to generate panels of antibodies against a list of criteria that learn from molecules in current development and add other attributes that potentially improve therapeutic efficacy and reduce development risk.”
IONTAS will receive undisclosed development and clinical milestone payments on each of the ADCs. Glythera will be responsible for the development, manufacturing and commercialization of any ADC products resulting from the agreement.
“Ultimately both companies are aiming to enter the clinic with therapeutics developed from their respective platforms with a particular focus on the treatment of solid tumors. We also see the process of antibody discovery and ADC generation becoming more streamlined as both partners better understand the needs of each other. In the long term, this will facilitate rapid preclinical development and quicker access to the clinic,” note Butt and Evetts. “We are excited about the ability to develop industry-leading ADCs based on IONTAS’ expertise in antibody generation and Glythera’s novel conjugation platform. It will also be of interest to understand more about the best combination of antibody and toxin within the development of ADCs. By applying a stable conjugation technology such as PermaLink with antibody and toxin panels, each project will result with ‘more shots on goal’ and hopefully more efficacious therapeutics.”
“First-generation ADCs have helped to push the boundaries of cancer treatment for a number of sufferers. We believe that this collaboration and the strategies behind it can raise the bar by developing more effective, better tolerated ADCs for cancers that are typically associated with poor prognosis,” conclude Butt and Evetts.

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