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Adcs and Solid Tumours the Payload Revolution That Drives Therapeutic Opportunities in Unmet Need

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Adcs and Solid Tumours the Payload Revolution That Drives Therapeutic Opportunities in Unmet Need Therapeutics ADCs and solid tumours the payload revolution that drives therapeutic opportunities in unmet need The fight against cancer is ongoing. Despite progress in many indications, mortality rates for some of the most difficult to treat solid tumour types have not improved substantially since the early 1970s. By Dr Jenny Thirlway en-year survival statistics for oesophagus 90 ADCs in clinical trials as of January 20202. The and lung cancer have shown an increase of global market for ADCs is anticipated to reach Tless than 10% and pancreatic cancer has $7.5 billion by 2025. shown no improvement in survival rates at all1. First generation ADCs suffered from a lack of Even for cancers where survival rates have potency, as existing chemotherapeutic agents with improved, such as malignant melanoma, breast known toxicity profiles such as methotrexate, vin- and uterine, there is still a need for more effica- blastine and doxorubicin were conjugated in an cious treatments which importantly, do not come effort to increase their specificity. The cBR96-dox- with debilitating side effects. orubicin conjugate showed promise in pre-clinical Antibody Drug Conjugate (ADC) technology studies and progressed to a Phase II clinical trial but has been the focus of intense interest as a means to was insufficiently efficacious. The effectiveness of an provide selective tumour killing with increased effi- ADC depends on efficiency of internalisation and cacy and fewer side-effects than standard of care the failure of this conjugate was largely attributed to chemotherapies. ADCs comprise a monoclonal under-potency of the doxorubicin payload. It is esti- antibody (or antibody fragment) that targets a mated that 4-12 million doxorubicin molecules are tumour-associated antigen, conjugated via a chem- required to kill a cell. Antigen expression levels are ical linker to a highly cytotoxic entity. Binding of generally less than one million copies per cell mak- the antibody to the cell surface triggers internalisa- ing it difficult to achieve a critical concentration of tion, and processing within endosomes or lyso- toxin3. Lessons from the story of cBR96-doxoru- somes releases the potent cell-killing molecule. bicin established the use of more potent cytotoxic Combining the targeting power of an antibody payloads to counteract issues with payload delivery. with a potent cytotoxic agent makes it possible to The first ADC to be approved, Mylotarg® for eradicate cancer cells more effectively and selec- treatment of acute myelogenous leukaemia (AML), tively, while reducing the side-effects which under- is conjugated to calicheamicin. Mylotarg® was mine patient quality of life. Currently, seven ADCs originally approved by the FDA in 2000 and sub- have been approved (four for haematological can- sequently withdrawn in 2010 following an unsuc- cers and three for solid tumours) and the clinical cessful confirmatory Phase III trial4. Calicheamicin and commercial potential of ADC technology is is a potent anti-tumour antibiotic that associates reflected in the burgeoning pipeline, with around with the minor groove of DNA causing double 24 Drug Discovery World Spring 2020 Therapeutics Mechanism of action of ADCs strand DNA breaks. The failure of Mylotarg® was bind to the ‘plus’ end of growing microtubules partly attributed to an unstable linker that released blocking polymerisation of tubulin dimers. Two out payload prematurely. It was reapproved by the of three approvals of ADCs in solid tumours FDA in September 2017 and by the EMA in April employ tubulin inhibitors as the payload. Kadcyla® 2018 on an altered dosing regimen. Another was approved by the FDA in February 2013 for the calicheamicin-based ADC, Besponsa®, was also treatment of Her2 positive metastatic breast cancer approved in 2017 for the treatment of relapsed or and is comprised of the anti-Her2 antibody refractory acute lymphoblastic leukaemia, but trastuzumab conjugated to the maytansine DM1. three other calicheamicin ADCs in development Padcev™ was granted accelerated approval by the have been discontinued due to having a very nar- FDA in December 2019 for treatment of locally- row Therapeutic Index (TI). advanced or metastatic urothelial cancer and is con- Around 40% of clinically-active ADCs employ jugated to the auristatin MMAE. tubulin inhibitors from the auristatin and maytan- Tubulysins have been developed as next genera- sine classes5. Auristatins are derived from dolas- tion tubulin inhibitors. Tubulysins bind to the tatin 10, isolated from the marine sea hare vinca binding site of tubulin and exhibit potent Dolabella auricularia. They block tubulin assembly cytotoxic activity in the picomolar (pM) range. and cause G2/M phase cell cycle arrest. One of the Unlike the auristatins and maytansines, tubulysins first ADCs to be approved, Adectris®, for treatment have been shown to bypass drug efflux pumps and of Hodgkin lymphoma and systemic anaplastic retain potency in MDR1 expressing cell lines6. large cell lymphoma, is conjugated to Monomethyl Three out of four of the tubulysin-based conjugates auristatin E (MMAE), as is Polivy™ for the treat- (two Small Molecule Drug Conjugates and one ment of relapsed refractory diffuse large B cell lym- ADC) to have entered the clinical development phoma. Maytansine was isolated from the bark of phase have been discontinued due to either safety the African shrub Maytenus ovatus and is a potent or efficacy reasons. inhibitor of microtubulin assembly. Maytansines Although first-generation tubulin inhibitors Drug Discovery World Spring 2020 25 Therapeutics A structural model of an Antibody Drug Conjugate (photograph courtesy of Iksuda Therapeutics) have been approved in several indications, they are to the nucleophilic C2-amino group of a guanine not as effective in indications with lower expres- base and are 600 times more potent than PBD sion of target antigen or cells that are less sensitive monomers in vitro. As with tubulysins, PBDs avoid to tubulin inhibition. It has become clear that there MDR1 mediated drug resistance7. The first PBD is a need for payloads with increased potency and dimer-based ADCs entered the clinic in 2013. alternative mechanism of action to the tubulin Vadastuximab talirine targets CD33 which is over- inhibitor class. There has therefore been a push expressed in AML. Pre-clinically vadastuximab towards the design of payloads to address targets talirine was shown to be more potent than where tubulin ADCs are proving to be insufficient- Mylotarg® against a panel of AML cell lines and ly active, such as colon cancer. primary AML cells in vitro and in vivo. Unlike Third-generation ADCs have looked to payloads Mylotarg®, anti-leukaemic activity was observed with novel modes of action and activity against in AML models with the multidrug-resistant phe- non-proliferating cells so targets can be widened to notype8. However, in June of 2017 Seattle Genetics include tumour initiating cells (TICs). Higher announced the discontinuation of the Phase III potency allows for targeting of antigens with rela- CASCADE clinical trial of vadastuximab talirine tively low tumour expression levels. (SGN-CD33A) in frontline older AML patients fol- Pyrrolobenzodiazepines (PBD) are based on nat- lowing consultation with the Independent Data urally-occurring, anti-tumour antibiotics that bind Monitoring Committee (IDMC) and after review- to the DNA minor groove in a sequence-specific ing unblinded data. The data indicated a higher manner. PBD dimers can form interstrand and rate of deaths, including fatal infections in the intrastrand DNA cross-links by covalently binding vadastuximab talirine-containing arm versus the 26 Drug Discovery World Spring 2020 Therapeutics control arm of the trial. In March 2018 Seattle tivity reaction (7%) and pleural effusion (5%)9. Genetics announced it was no longer developing The development of Rova-T was discontinued in vadastuximab tailrine as a result of recent portfolio August 2019 after the IDMC recommended termi- and resource prioritisation decisions. nating the Phase III MERU study due to lack of Rovalpituzumab tesirine (Rova-T) targets cancer survival benefit. stem cell-associated target delta-like protein 3 Since 2013, 20 PBD dimer-based ADCs have (DLL3) which is over-expressed in small cell lung entered clinical development with eight being dis- cancer (SCLC), a solid tumour with few treatment continued. The apparent narrow TI of PBD dimer- options. In Phase I/II studies of relapsed SCLC based drugs has led to a shift away from cross-link- patients who had previously failed one or more ers towards DNA monoalkylators such as the standard therapies, Rova-T demonstrated overall indolinobenzodiazepine pseudodimers (IGNs) and response rates of 44% in the patients identified duocarmycins. with high expression of DLL3. Based on these Within the IGN class, it was discovered that the results, in 2016 Abbvie announced that it would cross-linking analogues had an unfavourable toxi- acquire Stemcentrx and its lead late-stage asset city profile in mice with the animals displaying rovalpituzumab tesirine in a deal worth upwards prolonged body weight loss, as well as delayed of $9 billion. By 2018, things were looking less lethality. Development of a DNA alkylating IGN promising when disappointing results were payload that does not have cross linking capability announced for the Phase II TRINITY trial. An provided a distinct mode of action compared with independent review committee assessed efficacy as that of the PBDs. In vivo testing revealed that the an overall response rate of 16% (95% CI, 11, 22) alkylating IGN ADC did not display any signs of with the most common (≥5%) grade ≥3 severe tox- prolonged or delayed toxicity10. icities being thrombocytopenia (11%), photosensi- To date, there are four pre-clinical IGN-based Empower Your Research With IncuCyte® Live-Cell Analysis The IncuCyte® Live-Cell Analysis System speeds scientific discovery by combining lab-tested protocols and reagents with powerful, automated image acquisition and analysis. Gain dynamic insights into the health, morphology, movement and function of cell models, all from the stable environment of a tissue culture incubator.
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