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

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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

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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

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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

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Drug Discovery World Spring 2020 27 Therapeutics

References ADCs and three have entered clinical trials. assessed in a Phase III trial in patients with Her-2- 1 Cancer Research UK, IMGN779 was the first IGN-based ADC to enter positive locally-advanced or metastatic breast can- https://www.cancerresearchuk. clinical trials in 2016. In 2018 Immunogen report- cer11. Trastuzumab duocarmazine is essentially a org/health-professional/cancer- ed that IMGN779 displayed tolerability with ‘biobetter’ version of Kadcyla®. Kadcyla® is statistics/survival/common- cancers-compared. Accessed repeat dosing across a wide range of doses in approved for the treatment of Her2 positive February 2020. patients with relapsed AML. One Dose Limiting metastatic breast cancer defined by immunohisto- 2 Beacon ADC Digest: January Toxicity was reported and Adverse Events were chemistry testing as being 3+. Based on these crite- 2020, A Landscape Review. © consistent with underlying disease. No cumulative ria 20-25% of metastatic breast cancer patients Hanson Wade, January 2020. toxicity was observed following multiple doses (up would be eligible for treatment with Kadcyla®. 3 Khera, E and Thurber, GM. Pharmacokinetic and to 40). IMGN779 demonstrated anti-leukaemia Trastuzumab duocarmazine aims to extend the tar- Immunological Considerations activity in 41% (12 of 29) patients with evaluable get population to patients with lower Her2 expres- for Expanding the Therapeutic bone marrows (≥ 0.39mg/kg). However, the com- sion levels12. Window of Next-Generation pany discontinued the development of IMGN779 Kadcyla® surpassed $1 billion in annual sales Antibody-Drug Conjugates, in June 2019 following portfolio prioritisation and last year, becoming the first ADC to hit block- BioDrugs 32(5): 465-480, 2018. 4 Petersdorf, SH et al. A Phase restructuring initiatives. buster status, so there are obvious incentives to 3 study of gemtuzumab Immunogen has another IGN-based ADC in develop biobetter versions. The most recently- ozogamicin during induction clinical trials in collaboration with Jazz approved ADC, Enhertu®, is another trastuzumab- and post-consolidation therapy Pharmaceuticals. IMGN632 is being developed for based ADC (trastuzumab deruxtecan). In this case in younger patients with acute patients with relapsed AML, Blastic Plasmacytoid the cytotoxic moiety is the topoisomerase inhibitor myeloid luekemia, Blood 121: 4854-4860, 2013. Dendritic Cell Neoplasm and other CD123 posi- I inhibitor, deruxtecan. 5 Beacon ADC Digest: August tive haematologic malignancies. In 2019 the FDA The topoisomerase I inhibitors employed in 2019, Payloads for ADCs. © granted Orphan-Drug Designation for IMGN632 ADCs are camptothecin analogues. Camptothecin Hanson Wade, August 2019. as a treatment for AML. Data presented at ASH in was originally isolated from the Chinese ornamen- 6 Tumey, LN et al. 2019 showed that IMGN632 displays a tolerable tal tree Camptothecaacuminata in the 1980s. Optimization of tubulysin antibody-drug conjugates: A safety profile and activity at doses up to 0.3mg/kg Deruxtecan (also known as DX-8951 derivative, case study in addressing ADC and a dose and schedule of 0.045mg/kg given on DXd) is a more water-soluble analogue of camp- metabolism. ACS Med. Chem. day one every three weeks has been selected for tothecin and SN38 is an active metabolite of Let.: 7(11): 977-982. Phase II development. In the assessable AML pop- irinotecan which is a semi-synthetic analogue of 7 Fu, Y and Ho, M. DNA ulation (n = 66), 37 (55%) had a reduction in bone camptothecin. Camptothecin analogues form a sta- damaging agent-based antibody-drug conjugates for marrow blasts and 13 (20%) achieved an objective ble complex with human DNA topoisomerase I cancer therapy. Antibody response across all dose levels. Three of seven and DNA, which induces DNA damage and initi- Therapeutics 1(2): 43-53, 2018. evaluable BPDCN patients (43%) achieved a ates the cell apoptosis pathway7. There are cur- 8 Kung Sutherland, MS et al. response after a single dose of IMGN632. rently 12 topoisomerase inhibitor-based ADCs in SGN-CD33A: a novel CD33- TAK164 is an IGN-based ADC targeting Guanyl the development pipeline. These are lower potency targeting antibody-drug conjugate using a Cyclase C in solid tumour indications. Clinical trial cytotoxics and are therefore more suitable than the pyrrolobenzodiazepine dimer NCT03449030, A Study of TAK-164 in Participants DNA cross linkers/alkylating compounds for anti- is active in models of drug- with Advanced Gastrointestinal (GI) Cancer gen targets that have greater expression in normal resistant AML. Blood Expressing Guanylyl Cyclase C (GCC), was initiated tissues. 122:1455-1463, 2013. in 2018 based on promising pre-clinical data in cell Daiichi-Sankyo’s Enhertu® was granted acceler- 9 Harris, J. Rova-T Delivers Disappointing Results in Phase line-derived and patient-derived xenograft models. ated approval by the FDA for the treatment of II SCLC Trial. Targeted Oncol The success of the IGNs is dependent on the pay- Her2 positive metastatic breast cancer in 2018, https://www. load class being able to overcome the TI issues of December 2019 and is notable for being the first targetedonc.com/news/rovat- the PBD class of payload. The ADC community ADC to be approved for solid tumour indications delivers-disappointing-results- will be monitoring the progress of the IGN-based that does not employ the tubulin inhibitor payload in-phase-ii-sclc-trial. 10 Miller, ML et al. A DNA- ADCs with interest. class. Approval was based on results from the DES- Interacting Payload Designed The duocarmycins were initially isolated from TINY-Breast01 (NCT03248492) trial. The main to Eliminate Cross-Linking Streptomyces zelensis in the late 1970s. efficacy outcome measures were confirmed objec- Improves the Therapeutic Duocarmycins have pM potency and bind to the tive response rate (ORR) assessed by independent Index of ADCs. Mol. Cancer minor groove of DNA in a sequence selective man- central review. ORR was 60.3% (95% CI: 52.9, Ther. 17(3): 650-660, 2018. ner forming a covalent linkage to the N3 of ade- 67.4), with a 4.3% complete response rate and a nine. Currently there are five duocarmycin-based 56% partial response rate. Median response dura- ADCs in the development pipeline, predominantly tion was 14.8 months (95% CI: 13.8, 16.9). concentrating on solid tumour indications. Earlier in 2019, Daiichi-Sankyo announced a glob-

The furthest progressed duocarmycin-based al development and commercialisation collabora-

Continued on page 29 ADC is trastuzumab duocarmazine which is being tion with AstraZeneca. AstraZeneca is set to pay

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Daiichi Sankyo up to $6.9 billion in total consider- with high potency and novel mechanism of action Continued from page 28 ation, including a $1.35 billion upfront payment with the aim of building the next generation of and up to an additional $5.55 billion contingent ADCs to treat the broadest patient population 11 Xu, Z et al. Novel HER2- Targeting antibody-drug upon achievement of future regulatory and sales possible. DDW conjugates of trastuzumab milestones. The companies will share equally beyond T-DM1 in breast development and commercialisation costs as well cancer: Trastuzumab as profits worldwide from Enhertu® with Daiichi Deruxtecan (DS-8201a) and Sankyo maintaining exclusive rights in Japan. (Vic-)Trastuzumab duocarmazine (SYD985), Eur. J. One of the next ADCs on track for approval is Med. Chem., 2019. Sacituzumab govitecan which is currently in Phase 12 van der Lee, M et al. The III trials for several solid tumour types. Preclinical Profile of the Sacituzumab govitecan is comprised of an anti- Duocarmycin-Based HER2- Trop2 antibody conjugated to the irinotecan Targeting ADC SYD985 Predicts for Clinical Benefit in derivative SN38. Immunomedics’ Biologics Licence Low HER2-Expressing Breast Application (BLA) submission for the treatment of Cancers. Mol. Cancer Ther. metastatic triple-negative breast cancer was origi- 14(3): 692-703, 2015. nally rejected by the FDA due to unresolved manu- 13 Bardia, A et al. Sacituzumab facturing issues. In December 2019 Immunomedics Govitecan-hziy in Refractory Metastatic Triple-Negative announced the FDA acceptance of its BLA resub- Breast Cancer. N. Engl. J. Med. mission for sacituzumab govitecan to treat 380 (8): 741-751, 2019. metastatic triple-negative breast cancer. A Phase I/II 14 Pahl, A et al. Amanitins and clinical trial (NCT 01631552) showed efficacy with their development as a payload a 33% response rate, including complete responses for antibody-drug conjugates, Drug Discov. Today Technol. in three patients (2.8%) in a heavily-pretreated 30: 85-89, 2018. population of patients with metastatic triple-negative breast cancer. The clinical benefit rate (including stable disease for at least six months) was 45.4%. Diarrhoea and myelosuppression were the primary adverse events, and discontinuation rates were low13. Amanitin-based ADCs represent a new class of ADC using a novel mode of action. Alpha and beta-amanitins were identified more than 40 years ago in the green death cap mushroom Amanita Phalloides. Amanitins bind with highest affinity to eukaryotic RNA Polymerase II resulting in a dra- matic more than 1,000-fold decrease in transcrip- tion and protein synthesis. Amanitins are much more hydrophilic than other cytotoxic drugs and a consequence of this is that they do not passively penetrate the majority of human cells with the exception of hepatocytes. Kidney toxicity is also an issue for amanitins due to this being the excretion route. Heidelberg Pharma is developing amanitin- based ADCs which have potency in the pM range across a number of cell lines14. There are currently eight amanitin-based ADCs in pre-clinical development, predominantly in solid tumour indications. What does the future hold for the development Dr Jenny Thirlway leads Iksuda’s ADC proof payloads for solid tumour indications? ADCs grammes including the pre-clinical demonstration have traditionally been more successful in haema- of Iksuda’s proprietary PermaLink® conjugation tological malignancies but the advent of higher chemistry, exemplification of novel toxin platforms potency and novel mechanism of action toxins is and the evaluation of partnered antibodies/alterna- starting to bear fruit. Along with other companies tive scaffolds focused on the development of a in the field, Iksuda is working to develop payloads proof of concept stage ADC portfolio.

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