The thoughts below were contributed by one of the Guest Bloggers at the European Antibody Congress, held in November 2013. Read on for a wrap-up of this event, and to see this blogger's thoughts on the antibody sector at present, and where new and exciting developments could take place in years to come.
From the conference, the general discussion boiled down to mAbs and ADCs as the hot topic areas in oncology, with majority of the companies adopting the belief that in the next decade it'll still be naked mAbs that play a key role in cancer treatment, entering the pipeline more frequently and growing at a faster rate than the ADC market. Until all the idiosyncrasies of other approaches have been worked out, there will only be a shift towards other formats (e.g. ADCs) towards the end of that 10-year span (2018-2023), rapidly replacing mAbs. Some of the next generation technologies will be the real proof of concept of these longevities in the clinical settings.
ADC's are relevant right now because there are 2 commercial products on the market, and one of them is a landmark drug. There's a huge pipeline of products coming through, so due to the quality of clinical data and the number of companies looking at ADCs, this is becoming a very exciting area. The pharmaceutical industry tends go quiet in one area for a while, and then there'll be someone who's working away on a particular idea and all of a sudden they'll have a breakthrough – which is what happened with ADCs and now there is one on the market this has really ignited the interest again. So even though many antibody approaches have been around for some time and maybe made it or maybe not, it's difficult to predict where the field will go in the future, because it all depends on whether somebody has an idea that's slightly unthought-of. Naked mAbs haven't really lived up to their prospects, and that's another reason why its diverted more interest in ADC technology. There'll still be a steady stream of mAbs coming through but a few companies are just skipping mAbs all together and going straight to a conjugate because they're believed to have a greater response in the long run. Most of the cancer combination therapies tend to do much better, but complexity is one of the biggest hurdles to this concept. The regulatory hurdles for getting an ADC out are quite high, the obvious thing to do is to start mixing different drugs onto the ADC to try and hit more than one target on the cell.
A whole new generation of radionuclides with new alpha emitters are also coming through that scientists have found possible use in some special applications, but it's less well developed. Nanoparticles are very new with the first few enquiries coming through for this area, but there isn't a manufacturing process set up yet to really support it at the moment. Many technicians are coming out of the lab looking for CMO's and asking what can be done with these nanoparticles? Is it possible to form and conjugate? Nanotechnology in vivo is still very much unknown and there are significant toxicity issues due to accumulations of large particles, impacting antibody function, therefore risky from a safety perspective. Immunocytokines is an old concept that was poorly executed when it was first around but now there are better tools to make this work and it links very well with the old immune therapy part, but they could have immunogenicity problems. Immunocytokines have interesting responses from IL-2 conjugates in solid tumours with BsAbs becoming the logical extension of these approaches and/or multi-drug carrying ADCs.
Many of these technologies take years to develop, but the ones that are closest to success are the ADCs. The more antibodies that are moved into the clinic and studied for feedback from the biological perspective, the better it helps to design new molecules that enter the clinic, increasing chances of success. For example having only 5 in the clinic would be very risky, so it's important to have as many as possible and right now. ADCs have the most alternative style antibodies that are not all standard canonical full-length antibodies. Companies are making modified canonical antibodies e.g. protease-resistant molecules, antibody fragments and ones that have Fc modifications or enhanced ADCC or half-life. Some tumour cells express antigens that render them invisible to the immune system, so another approach that is getting a lot of noise at the moment are naked antibodies with immuno-modulatory activity. Immune cells express a molecule of PD1 and tumour cells then express the cell surface target, PDL1, turning off the immune system. Immuno-modulatory antibodies can interfere with this mechanism by either binding to PDL1 or PD1, blocking down-regulation and allowing immune-recognition of tumour, without killing tumour cell by ADCC. ADCs are becoming increasingly popular because many of the other approaches have been done before and although each has had their advantages, they have not shown much promise in the clinic. ADCs however, are showing promise in the clinic and there is huge investment for pharmaceuticals, biotech companies etc. Many new technologies are coming out and so ADCs will become more renowned in the next 5-10 years. Combinations of small molecules and antibodies will be most relevant with drugs that work through different mechanisms of action. Nanoparticles can target deep tumours and liposomes internalise inside the cell (balloon effect). Within the field of antibody cancer therapeutics, ADCs are a new class of agents, which are becoming increasingly attractive amongst both small and large pharmaceutical companies. The general concept of an antibody specifically delivering a chemotherapy drug to the exact tumour target, gives better guarantee of more efficient and effective treatment. The individual component parts that form an ADC have been around for many decades, so mAbs and cytotoxins would be referred to as traditional treatments, but it's the new generation of linker and payload technologies that have created opportunity to represent the new concept of modern therapeutics. Advantages of ADCs over traditional therapeutics is the ability to combine the benefits of the two individual components which complement each other and help to avoid some of the drawbacks associated with each when used as separate therapy. The guiding specificity of mAbs saves the death of healthy cells, thus resulting in minimal side effects and the drug provides the required potency for sufficient chemotherapy, shielded by the linker until it is cleaved by target cell components. This double action formula ensures target cell damage.
Cancer chemotherapy with ADCs in the past has observed Mylotarg approval (2000) followed by withdrawal (2010), approval of Adcetris (august 2011), becoming the only ADC available in 2012 and then recent approval of Kadcyla (February 2013). All three ADCs target cancer, Mylotarg against acute myelogenous leukaemia (AML), Adcetris for relapsed/ refractory hodgkin's lymphoma, but also anaplastic large cell lymphoma (ALCL), and Kadcyla as the first ADC against a solid tumour (HER2+ breast). Although companies are looking to extend indications of ADC use for different types of diseases, oncology still very much dominates the field of ADC and company development pipelines are growingly focused on cancer therapeutics. Pfizer for example have recently been working hard to advance their latest ADC chemistries involving "clinically validated natural products for conjugation to ADCs". In particular enediynes have been exemplified as a novel ADC payload, but different families of cytotoxics have the optimal pharmacology and MOA to be successful payloads, with great importance riding on mechanism, permeability, tractability, scalability, efflux and potency in cancer cells. ADC payload properties have great influence on ADC function and currently with a limited number of payloads and MOA's, natural product candidates can offer a wealth of new MOA's with even better permeability and diversity by biosynthetic engineering, increasing ADC potential. Most of the ADC products that are currently in the pipeline or market use proprietary ADC technology from two of the most active companies in the market, Seattle Genetics, manufacturer of Adcetris, with synthetic auristatins (MMAE or MMAF), and ImmunoGen, developers of TAP technology whereby antibody attached to multiple copies of a maytansinoid (DM1 or DM4). The two most common types of cytotoxins are, DNA damaging agents (calicheamycin) and tubulin polymerisation inhibitors (auristatins and maytansines). Since the failure of first generation ADCs was down to unstable acid-labile linkers causing systemic toxicity, linker technology has advanced in newer generations to improve stability of ADCs. These include disulphide linkers cleaved by thiols (glutathione and cysteine), peptide linkers cleaved by proteases, thioether linkers (non-cleavable but dispatch drug by degradation of antibody from conjugate), and more recently PEG4Mal linkers for targeting drug-resistant tumour cells.
[This blog was contributed by Anil Vaghela, Student (MPharm), King's College London].
If you're interested in the above, you might want to check out the European Antibody Congress 2014 – preparations are in full swing! If you've got any further thoughts on the antibody sector, get in touch or comment below.