Secrets to Successful ADC Development
Antibody-drug conjugates (ADCs) are an emerging class of medicines designed for high-specificity targeted delivery of therapeutic drugs. The main research area in oncology but ADCs are expanding beyond oncology into a wide range of indications where there is benefit in targeting delivery of a therapeutic agent to avoid unwanted off-target adverse effects. An ADC consists of three elements, the targeting component (typically a full-length antibody), a chemical linker to covalently bind the antibody to the third element with is the payload which has the therapeutic activity (typically a small molecule). The typical mechanism of action is for the antibody to recognise a target antigen specifically expressed on the target cell type and to localise the therapeutic payload to this cell type where it is internalised or released. The targeting can be tailored to be highly specific for the target cell only or to allow a bystander effect where cells in close proximity are also targeted. Selection of the antibody, the chemical linking method are the therapeutic payload are essential to the success of the ADC.
Historically ADCs have been based on existing monoclonal antibodies which were conjugated to extend their patent life or to try to resurrect failed antibody candidates which would selectively bind the target antigen but failed to elicit a significant therapeutic activity in clinical trials. This lead to some successes with Kadcyla which built on the success of Herceptin and Adcetris which took an existing antibody which failed to show any activity in Hogkin’s lymphoma but when conjugated with a potent cytotoxic generated significant success. This triggered an explosion of interest in the field and many other existing antibodies were selected for evaluation with platform drug technologies using the payloads from Kadcyla (maytansine) and Adcetris (Auristatin).
This approach looked to be very successful as early in vitro and in vivo data were outstanding and very few ADCs failed at early stages. Phase I data also continued the trend with very positive results which created further interest in the field. This lead to a rush of new entrants to the field with very few suppliers of ADC services. At this stage the ADC market had some big risks as the maturity of the ADC knowledge, understanding and experience was lagging far behind the excitement that had been generated. Over the last few years its becoming clear that some of the assumptions made were wrong and that has contributed to the higher attrition rate observed recently with some notable failures in the ADC space. There are three broad generations of ADC technology to date, the first used the existing antibody and platform payload model as already described, the second generation used the same payload platform but with antibodies designed to be conjugation (site specific conjugation) and the third uses specifically designed antibodies, linkers and payload. The first generation projects have shown a high rate of failure and are declining in most cases but there are still a few interesting candidates in late clinical stages. The second generation has not fared much better than the first and wasn’t a significant breakthrough, but the third generation shows more promise and is triggering more excitement again. While the third generation technology offers good promise for success, it also offers more challenges to adopt. Linkers and payloads are increasingly becoming specific to an individual project and that means that payloads that the payload production must be considered at the earliest stage of the project as there is no existing supply chain available. This means that projects will often be working with very small amounts of payload material at lower purity. It also means that generic analytical methods and processing steps are becoming less useful so development programs may be longer and more expensive. These new payloads may also come with more complex analysis, particularly around potency where existing cytotoxic cell killing assays traditionally used are not suitable.
Piramal is leading provider of ADC services and is well placed to see the challenges and issues in getting into this space. The main issue coming now is the increasing complexity observed in the projects. ADCs were already complex as they required the skills or both large molecule and small molecule development but they were some shortcuts by using the platform payload approaches. This option largely doesn’t exist now and all elements require development which complicates the supply chain and development significantly. We regularly help clients to navigate this space, often helping to consult and guide client through a highly complex development space where small errors can delay projects and consume budgets very rapidly. Piramal is aware of the budget and material constraints that restrain many clients programs and has the experience and skill to de-risk these critical steps as no other CMO can match Piramal’s 14 year track record in developing and commercialising ADCs. Piramal can also provide payload, conjugation, sterile fill and clinical trial distribution support to fully integrate these steps. Piramal can cover a wide range of payload types including the traditional cytotoxic payloads but also the new generation payloads through its North American sites in Toronto and Detroit, clinical and commercial conjugation activities in Grangemouth, Scotland and clinical and commercial sterile fill in Lexington, Kentucky. Integration of services is now a basic requirement for successful ADC development as the complexity of each step requires not just knowledge and experience but also significant co-ordination of the activities which is a huge burden on a developer to manage relationships between separate companies either individually or through informal alliances.