Antibody therapies have a little sister who is catching up in funding – and hype? In light of now five deaths from Juno’s CAR-T therapy, antibody drug conjugates are attracting a lot of interest in a resurgence after their debut 10 years ago. To feel out the field, we talked to two CEOs competing directly in the ADC space.
“Antibody drug conjugates were a really hot topic a few years ago, but they were overshadowed by immunotherapies. Now people are starting to realize that these therapies will not be the magic bullet,” says Jan Schmidt-Brand, CEO/CFO of Wilex, one of the leaders in the field of antibody drug conjugates. Some companies are upgrading immuno-oncology by combining antibodies with cytotoxins in what are known as antibody drug conjugates (ADCs).
While a magic bullet to cure cancer does not exist, ADCs might at least be an effective tool to fight it. “ADCs are highly efficient and, with adequate payloads, capable not only of overcoming tumor resistance but also killing dormant tumor cells that cause metastasis and tumor relapse,” says Schmidt-Brand. “Each ADC is something completely individual, regarding its target, indication, and chemistry: ADCs could theoretically be engineered to target just about any biological tumor target as long as it can be reached by internalizing antibodies.”
Moreover, ADCs stand to be easy to administer via infusion compared to CAR-T therapies, which entail a very complex procedure of blood withdrawal to extract T-cells, follow by genetic modification and amplification of these cells. This procedure amounts to financially and medically intensive care: the last estimated cost of the procedure was $500K per patient, and the patient needs to be closely monitored and cared for during the therapy. “It seems to be very effective in some indications, but still has a long way to go from a development perspective,” says Schmidt-Brand.
Are ADCs a good alternative? What are they exactly, and where are they going in Europe?
Is this yet another Immunotherapy? How ADC’s work
“ADCs aren’t really an immunotherapy in the common understanding of the term these days,” says Chris Martin, CEO of ADC Therapeutics. “They’re more of a guided missile, where the antibody is the guiding system of a cytotoxic payload.” In an ADC, a toxin piggybacks on an antibody as it homes in on its target receptor protein. The antibody sticks to the cell surface and is then internalized, payload and all, so the toxin can be released inside the cell to induce apoptosis.
The cytotoxic therapy on its own is simply chemotherapy, which carries serious side effects as it indiscriminately kills sick and healthy cells. This toxicity could theoretically be avoided by directing the molecules exclusively to the cancer cells; while medicinal chemistry aims to solve this problem by altering the molecule, the intrinsic specificity of antibodies could also provide an answer. “This is very much a way to marry the next generation of highly potent chemical drugs and the new generation of biologicals,” says Martin.
“We want to kill cancer cells and to keep killing them even if their characteristics change, but we also need to spare healthy tissue. Because a highly specific targeting system is embedded in antibody function, ADCs are an effective way to work through this problem,” says Martin. Schmidt-Brand agrees, “ADCs combine the best of two modalities, toxic efficacy and antibody specificity. The result is an improved therapeutic window with fewer side effects.”
However, the first generation was not successful in avoiding side effects, because unstable linkers between the toxin and the antibody caused the therapy to disintegrate before it reached its target. So how far have we come since then?
“We’re in Generation 3 of ADCs” – Progress to Perfection
The first ADC, Mylotarg (gemtuzumab-ozogamicin), hit the market in 2001 but was withdrawn in 2010 following a clinical trial that revealed patients died with no added benefits over standard cancer therapies. The fatal toxicity was caused by naked ozogamicin, which was released into patients’ bloodstreams when the linkers cleaved.
The linkers between the antibody and the payload thus turned out to be a subtle but key part of the technology, as they control distribution and delivery. Toxicity aside, unstable linkers make an ADC less effective and induce tumor resistance by exposing the cells to the toxin without effectively killing them.
“While patients initially responded well, the effect eventually wore off, rendering the treatment ineffective,” said Schmidt-Brand. Additionally, the first generation’s arbitrary lysine binding meant that control over toxin loading could only be realized with an average and led to a somewhat heterogeneous product.
In 2013, a second generation of ADCs began with Kadcyla and Adcetris. The new wave addressed the linker problems but exposed new pitfalls regarding toxin choice. Emtansine was a particularly problematic selection for Kadcyla because of its induction of multidrug resistance and reliance upon cells dividing rapidly, which left dormant cancer cells untouched. While neither Kadcyla nor Adcetris turned out to be a blockbuster on the level of Herceptin, which brought Roche €6Bn in 2015; the company reeled in €716M from Kadcyla the same year, while Seattle Genetics amassed €213M from Adcentris.
These therapies have done and still do a decent job in treating patients resistant to other standard treatments but they haven’t met the high expectations originally attached to them, according to Schmidt-Brand, which lead to general disappointment in ADCs. While biotech’s attention has been elsewhere, however, Seattle Genetics (SGN-CD33a) and Stemcentrx (Rova-T) are ushering in a third generation. AbbVie has bought in by acquiring Stemcentrx for €9.5Bn earlier this year.
Martin is also optimistic has perfected the ADC technology: “All of these problems – that is, drug purity, linkers and manufacturing – have now been solved in this third generation. Companies with the technologies to do so are seeing encouraging data in the clinic and before they start those trials, and that success is driving interest in the field,” he says.
Antibody or Toxin? Strategies in ADC Development
As antibody development has fallen under the purview of immuno-oncology, most companies are making their mark on the field via toxin development. For Martin, it seemed like a natural transition to the new generation of biological drugs from more traditional medicinal chemistry. Since founding Spirogen in 2000 to discover and develop new anticancer agents, Martin has built the company’s know-how into the strategy of ADC Therapeutics.
The company is known for its pyrrolobenzodiazepine (PBD) dimer toxins, which “block cell division without being caught by DNA repair mechanisms. This allows for long-term treatments,” explains Martin. Schmidt-Brand’s company, Wilex, focuses on amantin, which kills dividing and quiescent tumor cells by inhibiting RNA II Polymerase to effectively halt protein production.
Wilex is also looking at linkers. Schmidt-Brand says that “in most cases, you can use a certain toolbox of linkers, since linkers can change very different properties of the resulting ADCs in a sometimes unpredictable way. The best approach is to pick a small array of pre-selected linkers and then use the one yielding the best results.”
Fortunately, Martin says this is relatively easy to do since the screening “is relatively cheap at that stage and relatively fast to test a few tens of linkers. We understand quite a lot regarding the structure-activity relationships underlying linkers such that we have a rational pharmacokinetic approach, though admittedly it doesn’t cover everything.”
NBE Therapeutics is trying to hammer out a method that does cover everything so that any antibody can be matched to any toxin for any cancer. The company is working on enzymatic linkers in response to the shortcomings of Mylotarg and has submitted a patent application for its SMAC technology for site-specific conjugation of toxins to antibodies. With this selectivity, NBE hopes to introduce complete control of conjugation sites and ratios to control the payload.
Where does this leave us?
ADCs have a long way to go with clinical development, but they have already aroused a lot of optimism in cancer research. Schmidt-Brand believes that “the best is still to come with ADCs such that they will always be one of the targeted therapies to treat cancer.”
Martin sees the future of ADCs as intertwined with current research efforts in immuno-oncology. “ADCs will most likely be combined with checkpoint inhibitors to enhance the native immune system’s ability to identify and kill tumor cells. It will be an enormous clinical development to finally learn how to use these combinations or sequences effectively, and this will have a very significant impact on turning cancer from an acute to a chronic condition,” says Martin.
It’s not just the executives who are excited about the potential of ADCs: major investors have also jumped on board. ADC Therapeutics just raised this year’s largest round of a massive €94M last month, and for its part, NBE recently raised 20M CHF in Series B. As Schmidt-Brand notes, the leading investors are “people who know about these things: it was big pharma and big biotech who invested, so I would say they know what they’re paying for.” When I asked Martin for a comment, he agreed that AstraZeneca, who invested in the round, “is a highly informed investor.”
“These prices are just proof that ADCs are a hot topic with a rich future,” says Schmidt-Brand. Anticipating the failure of immuno-oncology to claim the title of ‘cancer cure’ alone, ADCs could be the missing piece to the puzzle: combining them with immuno-oncology could make it happen!
Images: extender_01, Juan Gaertner, nobeastsofierce, Kateryna Kon, Promotive / shutterstock.com
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