Major players in the rapidly advancing field of antibody drug conjugates (ADCs) will meet in London, United Kingdom, on 23-24 May for the annual ADC summit organized by SMI. This event has always been a high quality global event that showcases state-of-the-art innovations in the developments of ADCs as well as the latest to the clinical updates. Breakthrough areas and cutting-edge ADC technologies to be debated include novel conjugation technologies – key to the development of ADCs with higher therapeutic indices, next-generation payloads to improve efficacy and issues underlying the biology and mechanism of ADCs to help our understanding.
The opening keynote lecture will be given by MedImmune‘s Rakesh Dixit who will put into context the major advancements that the industry has learned to come up with the 5Rs of ADCs-The right target, right linker, right warhead, right antibody and right conjugation site to enhance the intratumor delivery of ADCs while minimizing serious adverse effects. The keynote presentation will discuss a successful biparatopic/bispecific ADC that utilizes unique mechanism of synergistic action in a very broad HER2 targeted space. The keynote for day two will be an overview of the successful marketed brentuximab vedotin (Adcetris®; Seattle Genetics/Takeda) given by Takeda’s global medical lead for that product.
Improving manufacturing and reducing toxicity
Presentations by Roger Breeli (NBE-Therapeutics), George Badescu (Abzena), Tomas Keating (ImmunoGen), Oleksandr Koniev (Syndivia) and Vijay Chudasama (UCL-Thiologics) will cover one of the most active areas of ADC development, conjugation technologies. Due to the large size and high number of conjugation positions/permutations of monoclonal antibodies (mAbs), technologies that lead to well-defined ADC drug substances are needed for better manufacturing as well as reduced toxicity of the higher conjugated aggregated species.
Many leading companies in ADC development (e.g., Pfizer, MedImmune, Genentech, etc.) have scanned the entire sequence of mAbs to come up with proprietary positions where additional cysteine thiols can be introduced in order to get site-specific conjugation based on thiol chemistry. Although the sequence space available is large, some antibody engineering is required. Disulphide-bridging technologies such as those from Abzena and UCL-Thiologics are more restricted as they are aimed at hinge thiols, but require no preliminary antibody engineering and offer advantages in terms of stability over conventional maleimide-based approaches.
Easy Enzymatic Formation
The sortase-mediated antibody conjugation (SMAC) technology from NBE-therapeutics is also more restricted in terms of position (C-terminii of antibody chains) and the requirement for antibody engineering, but makes up for this with the easy enzymic formation of stable peptide bonds with the payload. More recent innovations to be presented include conjugations based on the introduction of N-terminal serine hydroxyls functional groups for stable payload conjugation (Immunogen) and stable ‘APN’ linkers are tuned to release the payload in the tumour micro-environment (Syndivia).
Small molecule drug discovery still continues to be a source of innovation with many companies re-evaluating their archive of cytotoxics that were deemed too toxic to be developed as stand-alone chemotherapy drugs and the discovery of new, more potent payloads that can be safely incorporated. The innovation has to be in making such warheads conjugatable and releasable as components of ADCs.
With the two main class of microtubule inhibitors (MTI’s), maytansine and auristatin making up the approved payloads, other payload classes are moving up the development pathway. DNA damaging agents such as calicheamycin, SN38 and Pyrrolobenzodiazepines (PBDs) offer benefits in terms of modulating the therapeutic index (high and lower potency payloads) as well as overcoming drug-resistance issues seen in some cancers (e.g. colorectal) when exposed to MTIs. Iontcho Viahov (Endocyte) will describe novel and potent DNA cross-linking payloads and Jeremy Parker will unveil the latest developments from AstraZeneca’s Tubulysin program. Both speakers will focus on achieving total synthetic routes in order to generate reliable material for scale-up and manufacture.
Back to basics
Going back to some basic biological science to help our understanding of ADC action, Byoung-Chui Lee (Genentech) will describe a FRET assay that allows the payload release to be examined in sub-cellular detail. It is becoming clear that antibody binding and internalization are not the only steps that determine who effectively the payload is delivered to its final target as cytosolic transport can influence this parameter even if the payload is efficiently released. Investigators are also starting to consider the antibody format (whole IgG, Fab, smaller fragments) as a parameter for ADC design, with the vast majority of developers basing their ADCs on the whole immunoglobulin (IgG) format.
Ben-Fillippo Krippendorff (Roche) will discuss how an IgG-based ADC distributes into and clears from tissues and estimates how this may change with alternative formats that may have higher/faster tissue distribution kinetics. This could lead to next-generation ADCs having improved therapeutic indices. Indeed, this approach is the central platform for Mahendra Deonarain’s (Antikor Biopharma) technology that utilises antibody fragments (single-chain Fvs) as the ADC delivery vehicle. Termed FDCs (Fragment Drug Conjugates), Antikor will present data showing that smaller format ADCs can penetrate tumours more rapidly, clear from normal tissues more rapidly but due to the specifically-designed framework that can lead to high DAR (drug to antibody ratio), remain effective in curing tumours in xenograft models. High DAR is a bit of a contentious issue in the ADC field as people generally accept that high DAR leads to higher efficacy, but if the corresponding toxicity also increases by a similar/higher factor, the therapeutic index is no better or indeed worse.
Companies are trying to achieve higher DAR through improving linker-payload structure and conjugation strategies. Antikor achieves a high DAR on a smaller antibody fragment though choice of linker-payload and antibody engineering. The smaller format changes the conjugation kinetics compared to a whole antibody, which is known to aggregate when higher DARs are achieved. Debbie Mayer (Pfizer) will cover this important topic covering the impact of DAR on ADC properties using case studies.
Probably beyond the scope of Ben-Fillippo’s analysis would be Merrimak Pharmaceuticals’ nano-technology-ADCs. Here, much larger ADCs (around 100nm in diameter) are generated based on antibody-targeted, PEG-lipid-based nanoparticles that allow a high concentration of payload to be encapsulated. Payloads such as doxorubicin can be used without the associated cardio-toxicity. Products such as MM-302 (a HER2 targeted agent currently in Phase II clinical trials in breast cancer; NCT02213744) will be described.
A couple of novel early-stage ADCs will be described. Bayer’s BAY1129980 (anti-C4.4a/LYPD3) employs a novel auristatin payload and is targeted against solid cancers such as lung. It has just entered a phase I clinical trial, so an overbiew of the preclinical efficacy studies will be presented and an update on the early clinical trial will be given by Joerg Willunda (Bayer).
Another novel target is cadherin-6 (CDH6) expressed on ovarian and renal cancers. Carl Uli Bialucha (Novartis Institute for Biomedical research) will describe the lead selection strategy for the final choice of antibody-linker/payload and the PK/PD studies that gave an understanding of the mechanism of action and informed the projected dosing needed for downstream efficacy studies in ovarian patient-derived tumour models.
One of the final talks of the conference will be from Jens Lohrmann (Novartis) reviewing the challenges in ADC manufacture from a chemistry, manufacturing, and controls (CMC) context. Case studies will be used to illustrate conjugation scale up and site transfer (including the analytics) and how this influences the product quality.
This year, SMI’s 5th annual ADC Summit will be held in the Holiday Inn Kensington Forum and is expected to offer a wealth of information as well as learning and network opportunities.