- Email: [email protected]
Drawing lessons from the clinical development of antibody-drug conjugates
Drug Discovery Today: Technologies
Vol. 30, 2018
Editors-in-Chief Kelvin Lam – Simplex Pharma Advisors, Inc., Boston, MA, USA Henk Timmerman – Vrije Universiteit, The Netherlands DRUG DISCOVERY
TODAY
TECHNOLOGIES
Antibody – drug Conjugates (ADC)
Drawing lessons from the clinical development of antibody-drug conjugates Robert Lyon Protein Sciences, Seattle Genetics, Bothell, WA, USA
The antibody-drug conjugate (ADC) field has seen a remarkable expansion in the number of entrants in clinical studies. Many of these agents employ newer
Section editor: Dr. Vijay Chudasama – Department of Chemistry, University College London, London, UK.
conjugation technologies that have been developed over the last decade that confer various attributes to the ADCs prepared with them, including stability, potency, and homogeneity. In many cases, these new ADCs appear demonstrably superior to earlier technologies in preclinical models of activity and toxicology, but the degree to which these improvements will translate to the clinic is only starting to be seen. Many of these technologies are now competing head-to-head by targeting the same antigen in similar patient populations, allowing for a direct comparison of their clinical performance properties. As lessons from these experiences feed back into discovery research, future iterations of ADC design may be expected to bring improved therapeutics into the clinic.
The landscape of clinical-stage antibody-drug conjugates (ADCs) continues to expand and evolve. As of this writing there are four marketed products and at least 83 in clinical trials, with indications spanning the oncology space [1]. Of E-mail address: ([email protected])
these, nine are in advanced trials seeking their first approval and seven have received Breakthrough Therapy Designation from the FDA (Table 1). Clearly, the ADC modality has attracted considerable attention within the biopharmaceutical community and has yielded therapies that are having a positive impact in the treatment of cancer patients. ADCs are multicomponent therapeutics, combining the complexities of antibodies and small molecules, plus the chemistry involved in their conjugation. The rapid expansion of the ADC landscape has been accompanied by a robust preclinical exploration of many parameters in ADC design that may be expected to impact ADC pharmacology and toxicology. While not an exhaustive list, these include antigen and antibody characteristics, drug payload, linker cleavage chemistry, drug loading, site and homogeneity of conjugation, and stability properties. Advances in both chemistry and antibody engineering have provided the necessary tools to modulate these attributes and study their effects. For example, all four of the currently approved ADCs utilize conjugation to native amino acid residues, either cysteine or lysine. More recently, a variety of engineered constructs have entered the clinic, utilizing cysteine, nonnatural amino acids, or enzymatic recognition tags at specific
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Table 1. ADCs approved or in advanced trials. ADC a
Brentuximab vedotin (approved) Trastuzumab Emtansine (approved) Inotuzumab ozogamicina (approved) Gemtuzumab ozogamicin (approved) Sacituzumab govetican (IMMU-132)a Polatuzumab vedotina Enfortumab vedotina Trastuzumab deruxtecan (DS-8201a)a GSK2857916a Rova-T Mirvetuximab soravtansine Trastuzumab duocarmazine (SYD985) Depatuxizumab mafodotin a b
Lead indicationb
Antigen
Payload class
cHL, sALCL Breast (HER2+) ALL AML Breast (triple negative) NHL Bladder carcinoma Breast (HER2+) Multiple Myeloma Small cell lung carcinoma Ovarian carcinoma Breast (HER2+) Glioblastoma
CD30 HER2 CD22 CD33 Trop-2 CD79b CD22 HER2 BCMA DLL-3 FOLRa HER2 EGFRv3
Auristatin Maytansine Calicheamycin Calicheamycin Camptothecin Auristatin Auristatin Camptothecin Auristatin PBD Maytansine Duocarmycin Auristatin
Breakthrough Therapy Designation. cHL, classical Hodgkin lymphoma; sALCL, systemic anaplastic large-cell lymphoma; ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; NHL, non-Hodgkin lymphoma.
sites that allow for more deliberate control of the location, number, and distribution of payload drugs conjugated to the antibody [2]. On the payload side of the ADC, novel chemistries have been developed to link through a wider array of functional groups with ‘traceless’ release mechanisms [3–6]. While many of these new technologies have demonstrated superior properties in preclinical models, we are only now beginning to observe how well they translate to the clinical setting. The large number of ADCs that have now entered the clinic encompass a diverse set of characteristics arising from their underlying technology. As the clinical data mature, this situation will create a better opportunity for the field to understand how the various molecular attributes contribute to therapeutic performance. However, because of the multicomponent nature of ADCs there will be relatively few examples in which there is only one attribute that differs between two ADC candidates, thus allowing for the isolation of that variable and straightforward evaluation of its impact. Nevertheless, there are already several examples of multiple clinical-stage ADCs that share features in common, and these provide a starting point for understanding how these technologies have performed in humans. Ten years ago, the great majority of ADCs in development employed technology derived from just three sources: Wyeth/Pfizer (calicheamycins), Immunogen (maytansines), and Seattle Genetics (auristatins). These early-generation technologies have now been in clinical testing on antibodies targeting a variety of antigens across the oncology indication landscape. This is particularly true for the maytansine and auristatin technologies, owing to the outlicensing business model of the small biotech companies that developed them. At that time, these technologies were being deployed against a wide variety of antigens, with very few examples of the same antigen being targeted with two competing ADC technologies. This absence of ‘head-to-head’ comparisons of compet106
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ing technologies in the clinical space made it challenging to rigorously understand their relative merits. However, we can survey the results of many clinical studies on ADCs that use the same payload and conjugation technology to look for any patterns that emerge. It has been noted for instance that toxicities observed clinically tend to cluster according to the payload [7,8]. For example, ADCs delivering the auristatin payload MMAE tend to exhibit neutropenia and peripheral neuropathy, whereas ADCs using the maytansine DM1 are commonly associated with thrombocytopenia and hepatotoxicity. The frequent appearance of these dose-limiting adverse events across ADCs using the same payload but targeting a variety of antigens suggests that they are driven by antigen-independent processes. This may reflect the fact that the antigen selection process for ADCs has been very mindful of expression in healthy tissues or the potential of ADCs to inadvertently deliver drug to cells via antigen-independent mechanisms. Many such mechanisms have been proposed, including payload loss through drug-linker instability or cellular uptake of ADCs by normal cells via pinocytosis [9,10], through Fc receptors [11], or as a consequence of non-native physicochemical properties [12–14]. The anticancer activity observed in the clinic with many of these early-generation ADCs spawned the interest across the field to develop the many new technologies that are being evaluated in trials today. The pace of this development has outstripped the availability of known antigens deemed suitable for targeted drug delivery, resulting in many current examples of competing ADC technologies targeting the same antigen. This situation is beginning to allow us to observe more rigorous head-to-head comparisons of different ADC technologies in the clinical setting and perhaps to see more clearly how their attributes impact performance. One such example comes from Genentech’s efforts at targeting CD79b for patients with non-Hodgkin lymphoma. Their clinical development effort began with polatuzumab
Drug Discovery Today: Technologies | Antibody – drug Conjugates (ADC)
Vol. 30, 2018
vedotin (PoV), a native IgG1 conjugated to MMAE via native cysteine residues to an average of 3.5 drugs per antibody [15]. The technology behind this ADC is essentially the same as that used in most other MMAE ADCs, including Adcetris1 (brentuximab vedotin), enfortumab vedotin, and tisotumab vedotin. While PoV remains in clinical development and has received Breakthrough Therapy Designation status from the FDA in diffuse large B-cell lymphoma (DLBCL), Genentech elected to initiate clinical testing of a similar CD79b ADC, iladatuzumab vedotin (IV) [16]. Like PoV, this ADC employs a protease-cleavable MMAE drug-linker, but conjugated to the antibody utilizing Genentech’s ThiomabTM technology. This results in an ADC with a uniform drug-loading of 2 per antibody on engineered cysteine residues rather than a distributed drug loading centered near 4, and also creates a more stable chemical linkage between the antibody and the druglinker [17]. Both of these ADCs went through Phase I testing in relapsed or refractory B-cell non-Hodgkin’s lymphoma patients, including DLBCL, allowing a unique opportunity to see how this change in conjugation technology impacted clinical outcomes in a similar patient population [18,19]. A few key findings from these studies are summarized in Table 2. First, it is notable that the recommended Phase II doses for the ADCs are approximately proportional to their difference in drug loading. That is, reducing the number of drugs per antibody from 3.5 (PoV) to 2 (IV) produced a twofold increase in the recommended dose, resulting in a very similar dose of conjugated MMAE. Thus the reduction in drug loading and increased conjugation stability did not provide a great increase in the tolerability of the ADC on an MMAEdose basis. This was true despite the obvious differences in the tolerability profile—notably, the observation of significant ocular toxicity for IV that was absent for PoV. Although IV did appear to exhibit less of the neutropenia and peripheral neuropathy that has been a characteristic of MMAE ADCs, it seems to have traded that in exchange for blurred vision and corneal deposits. These types of reversible ocular toxicities have frequently been observed with ADCs employing other payloads, but have been uncommon with MMAE.
Finally, the overall response rates between the two ADCs appear similar, but the split between partial and complete responses seems shifted in favor of IV. These differences in activity and tolerability may arise from the greater chemical stability of IV, but may also be a consequence of the higher plasma concentrations of ADC that can be obtained by reducing the drug loading and thereby increasing the tolerated dose of antibody. The development path of IV and similar ThiomabTM ADCs remains to be determined. A second example of an antigen that is currently being targeted by multiple clinical-stage ADCs is Trop-2. Highly expressed in a variety of carcinoma indications, Trop-2 would seem to be an ideal ADC target but for its expression by normal epithelial cells in many tissues [20]. Despite this potential concern, Immunomedics began clinical testing of its Trop-2 ADC IMMU-132 in 2012. This ADC employs an SN38 payload (the active metabolite of the prodrug irinotecan) conjugated to native cysteine residues of sacituzumab at a uniform level of 8 drugs per antibody. An atypical feature of the drug-linker is the use of a labile carbonate functional group to release the active drug, resulting in an ADC with unusually low stability [21]. In clinical studies to date, IMMU132 has exhibited remarkable antitumor activity in triplenegative breast cancer, for which it has received Breakthrough Therapy Designation [22]. The ADC has also exhibited very favorable safety characteristics, with a toxicity profile similar to that observed with irinotecan but of lower severity, and no apparent evidence of Trop-2-mediated toxicity in antigen-positive normal tissues [23]. In 2014, Pfizer initiated clinical trials with a Trop-2 targeted ADC of its own (PF-06664178), and the results stand in stark contrast to the progress of IMMU-132. This ADC was armed with auristatin analog PF-06380101 conjugated in a homogeneous site-specific manner using transglutaminase to a drug loading of 2 per antibody [24]. This ADC design was intended to improve the antigen-independent safety profile by stabilizing the drug linkage and preventing the accelerated non-specific plasma clearance that can be observed with high drug loading. Findings from a phase 1 study of this agent were
Table 2. CD79b ADCs in the clinic. Polatuzumab vedotin [18]
Iladatuzumab vedotin [19]
Recommended Ph 2 dose
2.4 mg/kg q3w
4.8 mg/kg q3wb
Adverse events Neutropenia (any grade) Peripheral neuropathy (any grade) Blurred vision (any grade) Corneal deposits (any grade)
20/45 (44%) 16/45 (38%) Not observed Not observed
12/40 (30%) 6/40 (15%) 37.5% 27.5%
Responses in DLBCL Complete response Partial response
4/27 (15%) 10/27 (37%)
9/24 (38%) 4/24 (17%)
a b
a
Adverse event and response data shown for NHL patients receiving 2.4 mg/kg q3w. Adverse event and response data shown for patients receiving 2.4 mg/kg q3w. www.drugdiscoverytoday.com
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recently reported, and include only modest antitumor activity and an MTD of 2.4 mg/kg with intolerable skin rash and mucosal inflammation appearing along with neutropenia at higher doses [25]. This study was terminated early due to the observed toxicity and development of the ADC appears to have been discontinued. The authors of this Phase 1 study conclude that the skin and mucosal toxicity observed with PF-06664178 is likely to be Trop-2-mediated, and speculate as to why this agent exhibits antigen-dependent toxicity while IMMU-132 does not. In addition to using different antibodies, key differences in the ADC technology are the payload class and potency, drug loading, and drug-linker stability (Table 3). Given the number of parameters that differ between these ADCs, it is difficult to be certain which are most important in determining their very different clinical profiles. It is tempting to think that drug-linker stability may be a key differentiator, as it is rational to believe that loss of drug from the antibody would result in diminishing antigen-mediated drug delivery to normal tissues over time. Consequently, it may prove to be the case that ADC technologies with greater stability exhibit increased potential for target-mediated toxicities alongside the expected diminution in antigen-independent toxicity. This feature may put a greater burden on the selection of antigen to ensure an adequate therapeutic index for highly stable ADCs. Interestingly, Daiichi-Sankyo recently initiated a Phase 1 trial of DS-1062, a new Trop-2 ADC with characteristics very similar to IMMU-132, but with its exatecan payload conjugated through a stable peptide-cleavable drug-linker [26]. Data from this study should allow a comparison of clinical results between two agents with a closely matched
set of properties apart from stability, so the progress of DS1062 will warrant careful attention. A final example of multiple clinical-stage ADCs targeting the same antigen is found in the explosion of candidates for HER2+ cancers, summarized in Table 4. These ADCs have been the subject of two comprehensive recent reviews and the reader is referred to them for a thorough exploration of the characteristics of these agents [27,28]. In very recent developments, however, it would appear that two of these ADCs are no longer clinical candidates: ADC Therapeutics has announced the termination of ADCT-502, while MEDI4276 has been quietly removed from the publicly disclosed pipeline [29]. Of these agents, MEDI4276 is particularly notable as it represents perhaps the most highly engineered ADC to yet enter the clinic. Features of this ADC include a bispecific design to engage two separate epitopes of the HER2 antigen, cysteine mutations at two sites per heavy chain to allow for stable site-specific conjugation at 4 drugs per antibody, an additional heavy chain mutation to reduce Fcg receptor affinity (thought to contribute to off-target toxicity), and a novel tubulysin payload [30]. However, a recently published Phase 1 presentation abstract suggests that in the clinic, hepatotoxicity may have limited dosing to sub-optimal levels [31]. Given the many novel elements engineered into MEDI4276, it is difficult to be certain of the extent to which each of these features may have contributed to the toxicology profile. As the trials progress for the remainder of these HER2 ADCs, the resulting data may provide an unprecedented insight into the impact of ADC technology attributes on clinical outcomes within similar patient populations. How-
Table 3. TROP-2 ADCs in the clinic. ADC
Payload class
Payload potency
Drug loading
Linker stability
IMMU-132 PF-06664718 DS-1062
Camptothecin Auristatin Camptothecin
Nanomolar Picomolar Nanomolar
8 2 8
Low High Higha
a
The cleavage motif of DS-1062 is expected to be highly stable relative to IMMU-132, but may still be subject to a certain degree of drug-linker loss through maleimide elimination.
Table 4. HER2 ADCs in the clinic. ADC
Payload class
Notables
Trastuzumab emtansine Trastuzumab duocarmazine Trastuzumab deruxtecan XMT-1522 MEDI4276a ARX788 PF-06804103 RC48 ADCT-502a ALT-P7
Maytansine Duocarmycin Camptothecin Auristatin Tubulysin Auristatin Auristatin Auristatin Pyrolobenzodiazepine Auristatin
First approved solid tumor ADC First ADC with this drug-linker Native cyteine conjugation High drug loading through polymer conjugation Biparatopic antibody, site-specific conjugation Site-specific conjugation to a non-natural amino acid Site-specific conjugation
a
Discontinued programs.
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Conjugation through C-terminal engineered cysteine
Vol. 30, 2018
ever, investigators in the field should be wary of drawing general conclusions from specific experiences. For example, ADC designs that work well for unusually high-expressing antigens like HER2 and Trop-2 may not be successful for antigens with more modest expression levels. Likewise, a technology that works well in solid tumor carcinomas may be less successful in patients with hematologic indications such as leukemia. The evolution of the clinical-stage ADC pipeline will continue to inform ongoing technology development efforts by helping investigators to understand how various ADC characteristics contribute to therapeutic performance. With this accumulation of knowledge, there is every reason to expect continued refinement of the ADC concept into a therapeutic class with profound impact for patients with cancer.
References [1] Hanson Wade. (2018) ADC Beacon [database]. https://beacon-intelligence. com. [2] Schumacher D, Hackenberger CP, Leonhardt H, Helma J. Current status: site-specific antibody drug conjugates. J Clin Immunol 2016;36(Suppl. 1):100–7. [3] Burke PJ, Hamilton JZ, Pires TA, Setter JR, Hunter JH, Cochran JH, et al. Development of novel quaternary ammonium linkers for antibody-drug conjugates. Mol Cancer Ther 2016;15(5):938–45. [4] Staben LR, Koenig SG, Lehar SM, Vandlen R, Zhang D, Chuh J, et al. Targeted drug delivery through the traceless release of tertiary and heteroaryl amines from antibody-drug conjugates. Nat Chem 2016;8 (12):1112–9. [5] Kolakowski RV, Haelsig KT, Emmerton KK, Leiske CI, Miyamoto JB, Cochran JH, et al. The methylene alkoxy carbamate self-Immolative unit: utilization for the targeted delivery of alcohol-containing payloads with antibody-drug conjugates. Angew Chem Int Ed Engl 2016;55(28):7948–51. [6] Pillow TH, Schutten M, Yu SF, Ohri R, Sadowsky J, Poon KA, et al. Modulating therapeutic activity and toxicity of pyrrolobenzodiazepine antibody-drug conjugates with self-immolative disulfide linkers. Mol Cancer Ther 2017;16(5):871–8. [7] Donaghy H. Effects of antibody: drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. MAbs 2016;8(4):659–71. [8] Masters JC, Nickens DJ, Xuan D, Shazer RL, Amantea M. Clinical toxicity of antibody drug conjugates: a meta-analysis of payloads. Invest New Drugs 2018;36(1):121–35. [9] Zhao H, Gulesserian S, Ganesan SK, Ou J, Morrison K, Zeng Z, et al. Inhibition of megakaryocyte differentiation by antibody-drug conjugates (ADCs) is mediated by macropinocytosis: implications for ADC-induced thrombocytopenia. Mol Cancer Ther 2017;16(9):1877–86. [10] Zhao H, Atkinson J, Gulesserian S, Zeng Z, Nater J, Ou J, et al. Modulation of macropinocytosis-mediated internalization decreases ocular toxicity of antibody-drug conjugates. Cancer Res 2018;78(8):2115–26. [11] Uppal H, Doudement E, Mahapatra K, Darbonne WC, Bumbaca D, Shen BQ, et al. Potential mechanisms for thrombocytopenia development with trastuzumab emtansine (T-DM1). Clin Cancer Res 2015;21(1):123–33. [12] Lyon RP, Bovee TD, Doronina SO, Burke PJ, Hunter JH, Neff-LaFord HD, et al. Reducing hydrophobicity of homogeneous antibody-drug conjugates improves pharmacokinetics and therapeutic index. Nat Biotechnol 2015;33(7):733–5. [13] Strop P, Delaria K, Foletti D, Witt JM, Hasa-Moreno A, Poulsen K, et al. Sitespecific conjugation improves therapeutic index of antibody drug conjugates with high drug loading. Nat Biotechnol 2015;33(7):694–6. [14] Burke PJ, Hamilton JZ, Jeffrey SC, Hunter JH, Doronina SO, Okeley NM, et al. Optimization of a PEGylated glucuronide-monomethylauristatin E linker for antibody-drug conjugates. Mol Cancer Ther 2017;16(1):116–23.
Drug Discovery Today: Technologies | Antibody – drug Conjugates (ADC)
[15] Polson AG, Calemine-Fenaux J, Chan P, Chang W, Christensen E, Clark S, et al. Antibody-drug conjugates for the treatment of non-Hodgkin’s lymphoma: target and linker-drug selection. Cancer Res 2009;69(6):2358– 64. [16] Dornan D, Bennett F, Chen Y, Dennis M, Eaton D, Elkins K, et al. Therapeutic potential of an anti-CD79b antibody-drug conjugate: antiCD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma. Blood 2009;114(13):2721–9. [17] Junutula JR, Raab H, Clark S, Bhakta S, Leipold DD, Weir S, et al. Sitespecific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol 2008;26(8):925–32. [18] Palanca-Wessels MC, Czuczman M, Salles G, Assouline S, Sehn LH, Flinn I, et al. Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. Lancet Oncol 2015;16(6):704–15. [19] Herrera AF, Patel MR, Burke John M, Advani Ranjana H, Cheson Bruce D, Sharman Jeffrey P, et al. A phase I study of the anti-CD79b THIOMAB (TM)-Drug conjugate DCDS0780A in patients (pts) with relapsed or refractory B-cell non-Hodgkin’s lymphoma (B-NHL). Blood 2017;130:4129 [Conference abstract, presented at ASH 2017, Atlanta]. [20] Stepan LP, Trueblood ES, Hale K, Babcook J, Borges L, Sutherland CL. Expression of Trop2 cell surface glycoprotein in normal and tumor tissues: potential implications as a cancer therapeutic target. J Histochem Cytochem 2011;59(7):701–10. [21] Cardillo TM, Govindan SV, Sharkey RM, Trisal P, Goldenberg DM. Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys. Clin Cancer Res 2011;17(10):3157–69. [22] Breakthrough therapy designation for sacituzumab govitecan in triplenegative breast cancer. ADC Rev (online) )2016;(February). [23] Bardia A, Mayer IA, Diamond JR, Moroose RL, Isakoff SJ, Starodub AN, et al. Efficacy and safety of anti-Trop-2 antibody drug conjugate sacituzumab govitecan (IMMU-132) in heavily pretreated patients with metastatic triple-Negative Breast cancer. J Clin Oncol 2017;35 (19):2141–8. [24] Strop P, Tran TT, Dorywalska M, Delaria K, Dushin R, Wong OK, et al. RN927C: a site-Specific trop-2 antibody-drug conjugate (ADC) with enhanced stability, is highly efficacious in preclinical solid tumor models. Mol Cancer Ther 2016;15(11):2698–708. [25] King GT, Eaton Keith D, Beagle Brandon R, Zopf Christopher J, Wong Gilbert Y, Krupka Heike I, et al. A phase 1, dose-escalation study of PF06664178, an anti-Trop-2/Aur0101 antibody-drug conjugate in patients with advanced or metastatic solid tumors. Invest New Drugs 2018;36 (5):836–47. [26] Okajima D, Satoru Yasuda, Yusuke Yokouchi, Tomomichi Fujitani, Ken Sakurai JY, Michiko Kitamura. et al. Preclinical efficacy studies of DS1062a, a novel TROP2-targeting antibody-drug conjugate with a novel DNA topoisomerase I inhibitor DXd. J Clin Oncol 2008;36 (suppl; abstr e24206). [27] Hamblett KJ. HER2-Targeted ADCs: at the forefront of ADC technology development. In: Damelin M, editor. Cancer drug discovery and development. 2018. p. 163–85. [28] Trail PA, Dubowchik GM, Lowinger TB. Antibody drug conjugates for treatment of breast cancer: novel targets and diverse approaches in ADC design. Pharmacol Ther 2018;181:126–42. [29] Springer. (2018) AdisInsight [database]. https://adisinsight.springer.com/ drugs/800043545. [30] Li JY, Perry SR, Muniz-Medina V, Wang X, Wetzel LK, Rebelatto MC, et al. A biparatopic HER2-Targeting antibody-Drug conjugate induces tumor regression in primary models refractory to or ineligible for HER2-Targeted therapy. Cancer Cell 2016;29(1):117–29. [31] Pegram M, Hamilton E, Tan AR, Storniolo AM, Elgeioushi N, Marshall S, et al. Phase 1 study of bispecific HER2 antibody-drug conjugate MEDI4276 in patients with advanced HER2-positive breast or gastric cancer. Ann Oncol 2018;29(Suppl. 3):iii7–9 [Conference abstract, presented at TAT 2018, Paris].
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Vol. 30, 2018
Editors-in-Chief Kelvin Lam – Simplex Pharma Advisors, Inc., Boston, MA, USA Henk Timmerman – Vrije Universiteit, The Netherlands DRUG DISCOVERY
TODAY
TECHNOLOGIES
Antibody – drug Conjugates (ADC)
Drawing lessons from the clinical development of antibody-drug conjugates Robert Lyon Protein Sciences, Seattle Genetics, Bothell, WA, USA
The antibody-drug conjugate (ADC) field has seen a remarkable expansion in the number of entrants in clinical studies. Many of these agents employ newer
Section editor: Dr. Vijay Chudasama – Department of Chemistry, University College London, London, UK.
conjugation technologies that have been developed over the last decade that confer various attributes to the ADCs prepared with them, including stability, potency, and homogeneity. In many cases, these new ADCs appear demonstrably superior to earlier technologies in preclinical models of activity and toxicology, but the degree to which these improvements will translate to the clinic is only starting to be seen. Many of these technologies are now competing head-to-head by targeting the same antigen in similar patient populations, allowing for a direct comparison of their clinical performance properties. As lessons from these experiences feed back into discovery research, future iterations of ADC design may be expected to bring improved therapeutics into the clinic.
The landscape of clinical-stage antibody-drug conjugates (ADCs) continues to expand and evolve. As of this writing there are four marketed products and at least 83 in clinical trials, with indications spanning the oncology space [1]. Of E-mail address: ([email protected])
these, nine are in advanced trials seeking their first approval and seven have received Breakthrough Therapy Designation from the FDA (Table 1). Clearly, the ADC modality has attracted considerable attention within the biopharmaceutical community and has yielded therapies that are having a positive impact in the treatment of cancer patients. ADCs are multicomponent therapeutics, combining the complexities of antibodies and small molecules, plus the chemistry involved in their conjugation. The rapid expansion of the ADC landscape has been accompanied by a robust preclinical exploration of many parameters in ADC design that may be expected to impact ADC pharmacology and toxicology. While not an exhaustive list, these include antigen and antibody characteristics, drug payload, linker cleavage chemistry, drug loading, site and homogeneity of conjugation, and stability properties. Advances in both chemistry and antibody engineering have provided the necessary tools to modulate these attributes and study their effects. For example, all four of the currently approved ADCs utilize conjugation to native amino acid residues, either cysteine or lysine. More recently, a variety of engineered constructs have entered the clinic, utilizing cysteine, nonnatural amino acids, or enzymatic recognition tags at specific
1740-6749/$ © 2018 Elsevier Ltd. All rights reserved. https://doi.org/10.1016/j.ddtec.2018.10.001
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Table 1. ADCs approved or in advanced trials. ADC a
Brentuximab vedotin (approved) Trastuzumab Emtansine (approved) Inotuzumab ozogamicina (approved) Gemtuzumab ozogamicin (approved) Sacituzumab govetican (IMMU-132)a Polatuzumab vedotina Enfortumab vedotina Trastuzumab deruxtecan (DS-8201a)a GSK2857916a Rova-T Mirvetuximab soravtansine Trastuzumab duocarmazine (SYD985) Depatuxizumab mafodotin a b
Lead indicationb
Antigen
Payload class
cHL, sALCL Breast (HER2+) ALL AML Breast (triple negative) NHL Bladder carcinoma Breast (HER2+) Multiple Myeloma Small cell lung carcinoma Ovarian carcinoma Breast (HER2+) Glioblastoma
CD30 HER2 CD22 CD33 Trop-2 CD79b CD22 HER2 BCMA DLL-3 FOLRa HER2 EGFRv3
Auristatin Maytansine Calicheamycin Calicheamycin Camptothecin Auristatin Auristatin Camptothecin Auristatin PBD Maytansine Duocarmycin Auristatin
Breakthrough Therapy Designation. cHL, classical Hodgkin lymphoma; sALCL, systemic anaplastic large-cell lymphoma; ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; NHL, non-Hodgkin lymphoma.
sites that allow for more deliberate control of the location, number, and distribution of payload drugs conjugated to the antibody [2]. On the payload side of the ADC, novel chemistries have been developed to link through a wider array of functional groups with ‘traceless’ release mechanisms [3–6]. While many of these new technologies have demonstrated superior properties in preclinical models, we are only now beginning to observe how well they translate to the clinical setting. The large number of ADCs that have now entered the clinic encompass a diverse set of characteristics arising from their underlying technology. As the clinical data mature, this situation will create a better opportunity for the field to understand how the various molecular attributes contribute to therapeutic performance. However, because of the multicomponent nature of ADCs there will be relatively few examples in which there is only one attribute that differs between two ADC candidates, thus allowing for the isolation of that variable and straightforward evaluation of its impact. Nevertheless, there are already several examples of multiple clinical-stage ADCs that share features in common, and these provide a starting point for understanding how these technologies have performed in humans. Ten years ago, the great majority of ADCs in development employed technology derived from just three sources: Wyeth/Pfizer (calicheamycins), Immunogen (maytansines), and Seattle Genetics (auristatins). These early-generation technologies have now been in clinical testing on antibodies targeting a variety of antigens across the oncology indication landscape. This is particularly true for the maytansine and auristatin technologies, owing to the outlicensing business model of the small biotech companies that developed them. At that time, these technologies were being deployed against a wide variety of antigens, with very few examples of the same antigen being targeted with two competing ADC technologies. This absence of ‘head-to-head’ comparisons of compet106
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ing technologies in the clinical space made it challenging to rigorously understand their relative merits. However, we can survey the results of many clinical studies on ADCs that use the same payload and conjugation technology to look for any patterns that emerge. It has been noted for instance that toxicities observed clinically tend to cluster according to the payload [7,8]. For example, ADCs delivering the auristatin payload MMAE tend to exhibit neutropenia and peripheral neuropathy, whereas ADCs using the maytansine DM1 are commonly associated with thrombocytopenia and hepatotoxicity. The frequent appearance of these dose-limiting adverse events across ADCs using the same payload but targeting a variety of antigens suggests that they are driven by antigen-independent processes. This may reflect the fact that the antigen selection process for ADCs has been very mindful of expression in healthy tissues or the potential of ADCs to inadvertently deliver drug to cells via antigen-independent mechanisms. Many such mechanisms have been proposed, including payload loss through drug-linker instability or cellular uptake of ADCs by normal cells via pinocytosis [9,10], through Fc receptors [11], or as a consequence of non-native physicochemical properties [12–14]. The anticancer activity observed in the clinic with many of these early-generation ADCs spawned the interest across the field to develop the many new technologies that are being evaluated in trials today. The pace of this development has outstripped the availability of known antigens deemed suitable for targeted drug delivery, resulting in many current examples of competing ADC technologies targeting the same antigen. This situation is beginning to allow us to observe more rigorous head-to-head comparisons of different ADC technologies in the clinical setting and perhaps to see more clearly how their attributes impact performance. One such example comes from Genentech’s efforts at targeting CD79b for patients with non-Hodgkin lymphoma. Their clinical development effort began with polatuzumab
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vedotin (PoV), a native IgG1 conjugated to MMAE via native cysteine residues to an average of 3.5 drugs per antibody [15]. The technology behind this ADC is essentially the same as that used in most other MMAE ADCs, including Adcetris1 (brentuximab vedotin), enfortumab vedotin, and tisotumab vedotin. While PoV remains in clinical development and has received Breakthrough Therapy Designation status from the FDA in diffuse large B-cell lymphoma (DLBCL), Genentech elected to initiate clinical testing of a similar CD79b ADC, iladatuzumab vedotin (IV) [16]. Like PoV, this ADC employs a protease-cleavable MMAE drug-linker, but conjugated to the antibody utilizing Genentech’s ThiomabTM technology. This results in an ADC with a uniform drug-loading of 2 per antibody on engineered cysteine residues rather than a distributed drug loading centered near 4, and also creates a more stable chemical linkage between the antibody and the druglinker [17]. Both of these ADCs went through Phase I testing in relapsed or refractory B-cell non-Hodgkin’s lymphoma patients, including DLBCL, allowing a unique opportunity to see how this change in conjugation technology impacted clinical outcomes in a similar patient population [18,19]. A few key findings from these studies are summarized in Table 2. First, it is notable that the recommended Phase II doses for the ADCs are approximately proportional to their difference in drug loading. That is, reducing the number of drugs per antibody from 3.5 (PoV) to 2 (IV) produced a twofold increase in the recommended dose, resulting in a very similar dose of conjugated MMAE. Thus the reduction in drug loading and increased conjugation stability did not provide a great increase in the tolerability of the ADC on an MMAEdose basis. This was true despite the obvious differences in the tolerability profile—notably, the observation of significant ocular toxicity for IV that was absent for PoV. Although IV did appear to exhibit less of the neutropenia and peripheral neuropathy that has been a characteristic of MMAE ADCs, it seems to have traded that in exchange for blurred vision and corneal deposits. These types of reversible ocular toxicities have frequently been observed with ADCs employing other payloads, but have been uncommon with MMAE.
Finally, the overall response rates between the two ADCs appear similar, but the split between partial and complete responses seems shifted in favor of IV. These differences in activity and tolerability may arise from the greater chemical stability of IV, but may also be a consequence of the higher plasma concentrations of ADC that can be obtained by reducing the drug loading and thereby increasing the tolerated dose of antibody. The development path of IV and similar ThiomabTM ADCs remains to be determined. A second example of an antigen that is currently being targeted by multiple clinical-stage ADCs is Trop-2. Highly expressed in a variety of carcinoma indications, Trop-2 would seem to be an ideal ADC target but for its expression by normal epithelial cells in many tissues [20]. Despite this potential concern, Immunomedics began clinical testing of its Trop-2 ADC IMMU-132 in 2012. This ADC employs an SN38 payload (the active metabolite of the prodrug irinotecan) conjugated to native cysteine residues of sacituzumab at a uniform level of 8 drugs per antibody. An atypical feature of the drug-linker is the use of a labile carbonate functional group to release the active drug, resulting in an ADC with unusually low stability [21]. In clinical studies to date, IMMU132 has exhibited remarkable antitumor activity in triplenegative breast cancer, for which it has received Breakthrough Therapy Designation [22]. The ADC has also exhibited very favorable safety characteristics, with a toxicity profile similar to that observed with irinotecan but of lower severity, and no apparent evidence of Trop-2-mediated toxicity in antigen-positive normal tissues [23]. In 2014, Pfizer initiated clinical trials with a Trop-2 targeted ADC of its own (PF-06664178), and the results stand in stark contrast to the progress of IMMU-132. This ADC was armed with auristatin analog PF-06380101 conjugated in a homogeneous site-specific manner using transglutaminase to a drug loading of 2 per antibody [24]. This ADC design was intended to improve the antigen-independent safety profile by stabilizing the drug linkage and preventing the accelerated non-specific plasma clearance that can be observed with high drug loading. Findings from a phase 1 study of this agent were
Table 2. CD79b ADCs in the clinic. Polatuzumab vedotin [18]
Iladatuzumab vedotin [19]
Recommended Ph 2 dose
2.4 mg/kg q3w
4.8 mg/kg q3wb
Adverse events Neutropenia (any grade) Peripheral neuropathy (any grade) Blurred vision (any grade) Corneal deposits (any grade)
20/45 (44%) 16/45 (38%) Not observed Not observed
12/40 (30%) 6/40 (15%) 37.5% 27.5%
Responses in DLBCL Complete response Partial response
4/27 (15%) 10/27 (37%)
9/24 (38%) 4/24 (17%)
a b
a
Adverse event and response data shown for NHL patients receiving 2.4 mg/kg q3w. Adverse event and response data shown for patients receiving 2.4 mg/kg q3w. www.drugdiscoverytoday.com
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recently reported, and include only modest antitumor activity and an MTD of 2.4 mg/kg with intolerable skin rash and mucosal inflammation appearing along with neutropenia at higher doses [25]. This study was terminated early due to the observed toxicity and development of the ADC appears to have been discontinued. The authors of this Phase 1 study conclude that the skin and mucosal toxicity observed with PF-06664178 is likely to be Trop-2-mediated, and speculate as to why this agent exhibits antigen-dependent toxicity while IMMU-132 does not. In addition to using different antibodies, key differences in the ADC technology are the payload class and potency, drug loading, and drug-linker stability (Table 3). Given the number of parameters that differ between these ADCs, it is difficult to be certain which are most important in determining their very different clinical profiles. It is tempting to think that drug-linker stability may be a key differentiator, as it is rational to believe that loss of drug from the antibody would result in diminishing antigen-mediated drug delivery to normal tissues over time. Consequently, it may prove to be the case that ADC technologies with greater stability exhibit increased potential for target-mediated toxicities alongside the expected diminution in antigen-independent toxicity. This feature may put a greater burden on the selection of antigen to ensure an adequate therapeutic index for highly stable ADCs. Interestingly, Daiichi-Sankyo recently initiated a Phase 1 trial of DS-1062, a new Trop-2 ADC with characteristics very similar to IMMU-132, but with its exatecan payload conjugated through a stable peptide-cleavable drug-linker [26]. Data from this study should allow a comparison of clinical results between two agents with a closely matched
set of properties apart from stability, so the progress of DS1062 will warrant careful attention. A final example of multiple clinical-stage ADCs targeting the same antigen is found in the explosion of candidates for HER2+ cancers, summarized in Table 4. These ADCs have been the subject of two comprehensive recent reviews and the reader is referred to them for a thorough exploration of the characteristics of these agents [27,28]. In very recent developments, however, it would appear that two of these ADCs are no longer clinical candidates: ADC Therapeutics has announced the termination of ADCT-502, while MEDI4276 has been quietly removed from the publicly disclosed pipeline [29]. Of these agents, MEDI4276 is particularly notable as it represents perhaps the most highly engineered ADC to yet enter the clinic. Features of this ADC include a bispecific design to engage two separate epitopes of the HER2 antigen, cysteine mutations at two sites per heavy chain to allow for stable site-specific conjugation at 4 drugs per antibody, an additional heavy chain mutation to reduce Fcg receptor affinity (thought to contribute to off-target toxicity), and a novel tubulysin payload [30]. However, a recently published Phase 1 presentation abstract suggests that in the clinic, hepatotoxicity may have limited dosing to sub-optimal levels [31]. Given the many novel elements engineered into MEDI4276, it is difficult to be certain of the extent to which each of these features may have contributed to the toxicology profile. As the trials progress for the remainder of these HER2 ADCs, the resulting data may provide an unprecedented insight into the impact of ADC technology attributes on clinical outcomes within similar patient populations. How-
Table 3. TROP-2 ADCs in the clinic. ADC
Payload class
Payload potency
Drug loading
Linker stability
IMMU-132 PF-06664718 DS-1062
Camptothecin Auristatin Camptothecin
Nanomolar Picomolar Nanomolar
8 2 8
Low High Higha
a
The cleavage motif of DS-1062 is expected to be highly stable relative to IMMU-132, but may still be subject to a certain degree of drug-linker loss through maleimide elimination.
Table 4. HER2 ADCs in the clinic. ADC
Payload class
Notables
Trastuzumab emtansine Trastuzumab duocarmazine Trastuzumab deruxtecan XMT-1522 MEDI4276a ARX788 PF-06804103 RC48 ADCT-502a ALT-P7
Maytansine Duocarmycin Camptothecin Auristatin Tubulysin Auristatin Auristatin Auristatin Pyrolobenzodiazepine Auristatin
First approved solid tumor ADC First ADC with this drug-linker Native cyteine conjugation High drug loading through polymer conjugation Biparatopic antibody, site-specific conjugation Site-specific conjugation to a non-natural amino acid Site-specific conjugation
a
Discontinued programs.
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ever, investigators in the field should be wary of drawing general conclusions from specific experiences. For example, ADC designs that work well for unusually high-expressing antigens like HER2 and Trop-2 may not be successful for antigens with more modest expression levels. Likewise, a technology that works well in solid tumor carcinomas may be less successful in patients with hematologic indications such as leukemia. The evolution of the clinical-stage ADC pipeline will continue to inform ongoing technology development efforts by helping investigators to understand how various ADC characteristics contribute to therapeutic performance. With this accumulation of knowledge, there is every reason to expect continued refinement of the ADC concept into a therapeutic class with profound impact for patients with cancer.
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[15] Polson AG, Calemine-Fenaux J, Chan P, Chang W, Christensen E, Clark S, et al. Antibody-drug conjugates for the treatment of non-Hodgkin’s lymphoma: target and linker-drug selection. Cancer Res 2009;69(6):2358– 64. [16] Dornan D, Bennett F, Chen Y, Dennis M, Eaton D, Elkins K, et al. Therapeutic potential of an anti-CD79b antibody-drug conjugate: antiCD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma. Blood 2009;114(13):2721–9. [17] Junutula JR, Raab H, Clark S, Bhakta S, Leipold DD, Weir S, et al. Sitespecific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol 2008;26(8):925–32. [18] Palanca-Wessels MC, Czuczman M, Salles G, Assouline S, Sehn LH, Flinn I, et al. Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. Lancet Oncol 2015;16(6):704–15. [19] Herrera AF, Patel MR, Burke John M, Advani Ranjana H, Cheson Bruce D, Sharman Jeffrey P, et al. A phase I study of the anti-CD79b THIOMAB (TM)-Drug conjugate DCDS0780A in patients (pts) with relapsed or refractory B-cell non-Hodgkin’s lymphoma (B-NHL). Blood 2017;130:4129 [Conference abstract, presented at ASH 2017, Atlanta]. [20] Stepan LP, Trueblood ES, Hale K, Babcook J, Borges L, Sutherland CL. Expression of Trop2 cell surface glycoprotein in normal and tumor tissues: potential implications as a cancer therapeutic target. J Histochem Cytochem 2011;59(7):701–10. [21] Cardillo TM, Govindan SV, Sharkey RM, Trisal P, Goldenberg DM. Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys. Clin Cancer Res 2011;17(10):3157–69. [22] Breakthrough therapy designation for sacituzumab govitecan in triplenegative breast cancer. ADC Rev (online) )2016;(February). [23] Bardia A, Mayer IA, Diamond JR, Moroose RL, Isakoff SJ, Starodub AN, et al. Efficacy and safety of anti-Trop-2 antibody drug conjugate sacituzumab govitecan (IMMU-132) in heavily pretreated patients with metastatic triple-Negative Breast cancer. J Clin Oncol 2017;35 (19):2141–8. [24] Strop P, Tran TT, Dorywalska M, Delaria K, Dushin R, Wong OK, et al. RN927C: a site-Specific trop-2 antibody-drug conjugate (ADC) with enhanced stability, is highly efficacious in preclinical solid tumor models. Mol Cancer Ther 2016;15(11):2698–708. [25] King GT, Eaton Keith D, Beagle Brandon R, Zopf Christopher J, Wong Gilbert Y, Krupka Heike I, et al. A phase 1, dose-escalation study of PF06664178, an anti-Trop-2/Aur0101 antibody-drug conjugate in patients with advanced or metastatic solid tumors. Invest New Drugs 2018;36 (5):836–47. [26] Okajima D, Satoru Yasuda, Yusuke Yokouchi, Tomomichi Fujitani, Ken Sakurai JY, Michiko Kitamura. et al. Preclinical efficacy studies of DS1062a, a novel TROP2-targeting antibody-drug conjugate with a novel DNA topoisomerase I inhibitor DXd. J Clin Oncol 2008;36 (suppl; abstr e24206). [27] Hamblett KJ. HER2-Targeted ADCs: at the forefront of ADC technology development. In: Damelin M, editor. Cancer drug discovery and development. 2018. p. 163–85. [28] Trail PA, Dubowchik GM, Lowinger TB. Antibody drug conjugates for treatment of breast cancer: novel targets and diverse approaches in ADC design. Pharmacol Ther 2018;181:126–42. [29] Springer. (2018) AdisInsight [database]. https://adisinsight.springer.com/ drugs/800043545. [30] Li JY, Perry SR, Muniz-Medina V, Wang X, Wetzel LK, Rebelatto MC, et al. A biparatopic HER2-Targeting antibody-Drug conjugate induces tumor regression in primary models refractory to or ineligible for HER2-Targeted therapy. Cancer Cell 2016;29(1):117–29. [31] Pegram M, Hamilton E, Tan AR, Storniolo AM, Elgeioushi N, Marshall S, et al. Phase 1 study of bispecific HER2 antibody-drug conjugate MEDI4276 in patients with advanced HER2-positive breast or gastric cancer. Ann Oncol 2018;29(Suppl. 3):iii7–9 [Conference abstract, presented at TAT 2018, Paris].
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