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Antibody-Drug Conjugates in Clinical Trials for Lymphoid Malignancies and Multiple Myeloma Bo Yu1 and Delong Liu2,3*

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Antibody-Drug Conjugates in Clinical Trials for Lymphoid Malignancies and Multiple Myeloma Bo Yu1 and Delong Liu2,3* Yu and Liu Journal of Hematology & Oncology (2019) 12:94 https://doi.org/10.1186/s13045-019-0786-6 REVIEW Open Access Antibody-drug conjugates in clinical trials for lymphoid malignancies and multiple myeloma Bo Yu1 and Delong Liu2,3* Abstract Antibody-drug conjugates (ADC) represent a distinct family of chemoimmunotherapy agents. ADCs are composed of monoclonal antibodies conjugated to cytotoxic payloads via specialized chemical linkers. ADCs therefore combine the immune therapy with targeted chemotherapy. Due to the distinct biomarkers associated with lymphocytes and plasma cells, ADCs have emerged as a promising treatment option for lymphoid malignancies and multiple myeloma. Several ADCs have been approved for clinical applications: brentuximab vedotin, inotuzumab ozogamicin, moxetumomab pasudotox, and polatuzumab vedotin. More novel ADCs are under clinical development. In this article, we summarized the general principles for ADC design, and updated novel ADCs under various stages of clinical trials for lymphoid malignancies and multiple myeloma. Keywords: Antibody-drug conjugate, B cell maturation antigen, Brentuximab vedotin, Inotuzumab ozogamicin, Polatuzumab vedotin Introduction FDA-approved ADCs for lymphoid malignancies [8–11]. Monoclonal antibodies such as rituximab and obinutuzu- More ADCs are under clinical development over the mab are a major component in the combination regimens past decade. In this review, we discussed the general for the therapy of lymphoid malignancies [1–6]. Anti- principles of ADC design and updated on novel ADCs body-drug conjugates (ADC) are a new class of agents in in clinical trials for the treatment of lymphoid malignan- the treatment of various malignancies. ADC consists of cies and multiple myeloma. three fundamental elements: a tumor-specific monoclonal antibody (mAb), a cytotoxic small molecule referred to as Engineering ADCs payload, and a specialized chemical linker that connects Selection of antigens and antibodies the mAb and payload (Fig. 1). Upon binding to the corre- An ideal antigen for targeted therapy should have a high sponding antigen on the surface of tumor cells, the ADC/ copy number on tumor cells with limited or no expres- antigen complex is internalized and then the payloads are sion in normal tissues to minimize off-target ADC up- released, leading to cytotoxicity and cell death. ADC rep- take [12]. The antigen should be able to trigger resents a novel class of anticancer agents that theoretically intracellular internalization upon ADC binding. When enhance targeted killing of tumors while sparing normal an antigen target has heterogenous expression, optimal tissues, thereby maximizing efficacy and minimizing sys- antitumor activity relies more on the bystander effect, temic toxicity [7]. which is referred to as the ADC’s ability to diffuse across Brentuximab vedotin, inotuzumab ozogamicin, moxe- cell membranes and exert cytotoxicity on the neighbor- tumomab pasudotox, and polatuzumab vedotin are ing cells. This bystander effect is frequently influenced * Correspondence: [email protected] by the chemical nature of the payloads and linkers of the 2Department of Oncology, The First affiliated Hospital of Zhengzhou ADCs [13, 14]. University, Zhengzhou, China Immunoglobulin G (IgG) is the most frequently used 3Department of Medicine, New York Medical College and Westchester Medical Center, Valhalla, NY, USA subtype in ADCs due to the longer half-life, and the most Full list of author information is available at the end of the article chosen isotype is IgG1 [15]. IgG1 can induce stronger © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yu and Liu Journal of Hematology & Oncology (2019) 12:94 Page 2 of 17 Fig. 1 The schematic diagram of the structure of an antibody-drug conjugate. Antigens for the monoclonal antibody (mAb), linker types, and payloads that are in clinical development were listed antibody-dependent cell-mediated cytotoxicity (ADCC) tumor penetration capability, antitumor efficacy, and and complement-dependent cytotoxicity (CDC), which toxicity of an ADC [22]. further enhance the antitumor effect of ADCs [16]. How- The payloads commonly used in ADCs can be di- ever, the ADCC and CDC activities intrinsic to the anti- vided into two main categories: microtubule inhibi- bodies may add additional toxicities to the cytotoxic tors and DNA-damaging agents. Two currently payloads. One solution is to engineer the Fc portion of employed microtubule inhibitors are maytansinoids IgG1 heavy chain by introducing mutations to silent the and auristatins. Maytansinoids were initially derived intrinsic effector immune function [17]. IgG2 is believed from maytansine, a natural benzoansamacrolide dis- to conjugate more payloads because it contains four redu- covered in the plant maytenus ovatus [23]. There are cible interchain disulfide bonds, whereas IgG1 and IgG4 two maytansinoids derivatives: DM1 and DM4. DM1 in- have only two such bonds [18]. IgG4 has the tendency to cludes emtansine and mertansine. DM4 includes soravtan- exchange with other antibodies, therefore IgG4-based sine and ravtansine. Auristatins are extracted from the sea ADCs, such as inotuzumab ozogamicin, often contain a hare Dolabella auricularia. Two auristatin derivatives are stabilizing mutation in the hinge region to prevent half commonly used for ADC constructions: monomethyl aur- antibody exchange [19]. istatin E (MMAE, vedotin) and monomethyl auristatin F (MMAF, mafodotin) [24–31]. MMAE is toxic to the neighboring cells through the bystander effect due to its Characteristics of payloads neutral charge that allows diffusion across cell mem- The payloads used in ADCs are selected small mole- branes. MMAE has been used in brentuximab vedotin cules with high potency and proper hydropholicity and polatuzumab vedotin. MMAF lacks the ability of by- [20, 21]. Another important parameter is drug-anti- stander killing [32]. DNA-damaging agents include cali- body ratio (DAR), which is defined as the average cheamicin, pyrrolobenzodiazepines (PBD) dimer, number of payload molecules attached to a single indolinobenzodiazepines, duocarmycins, doxorubicin, etc. mAb. The ideal level of DAR is between 3 and 4. [33]. Calicheamicin has been used in inotuzumab ozoga- The DAR affects the drug stability in the circulation, micin and gemtuzumab ozogamycin [11, 34–36]. Yu and Liu Journal of Hematology & Oncology (2019) 12:94 Page 3 of 17 Linker selections and conjugation strategies (HL) [49], anaplastic large cell lymphoma (ALCL) cells, An ideal linker should not allow premature deconjuga- and a subset of cutaneous T cell lymphoma (CTCL) cells, tion in the circulation which triggers off-target toxicity. with limited expression on normal cells [50]. Linkers currently used in ADCs fall into two broad cat- Single-agent BV has been approved by the US FDA in egories: cleavable and non-cleavable linkers. Cleavable 2011 for the treatment of HL after failure of autologous linkers are sensitive to several intracellular conditions. stem cell transplantation (ASCT) or after failure of at least Here are some examples. Hydrazone, an acid-labile two prior multiagent chemotherapy regimens [8, 49, 51, 52] linker used in inotuzumab ozogamicin, can be selectively (Table 1). In a pivotal phase II trial (NCT00848926), 102 hydrolyzed in the acidic pH environment inside the lyso- patients with relapsed/refractory (R/R) HL who failed somes and endosomes. However, slow hydrolysis under ASCT were treated with intravenous BV 1.8 mg/kg every 3 physiologic condition in circulation has been reported weeks at a maximum of 16 cycles in the absence of disease [37]. Protease-cleavable linkers contain dipeptide se- progression or unacceptable toxicity. The overall response quences like valine-citrulline (Val-Cit) and valine-alanine rate (ORR) was 75% with 34% complete remission (CR) (Val-Ala) that can be recognized by cathepsin B. These and the median duration of response (DOR) was 6.7 linkers are often coupled with p-aminobenzyloxycarbonyl months. The most common treatment-emerging adverse (PABC) which serves as a spacer between the dipeptide events (TEAE) were peripheral sensory neuropathy (42%), and payload. Protease cleavable linkers show relatively nausea (35%), fatigue (34%), and neutropenia (19%). Fifty- higher stability in plasma. Val-Cit linker has been used to five percent of patients experienced grade ≥ 3 AEs (SAE), construct brentuximab vedotin [38]. Typical disulfide majority of which included neutropenia (20%) and periph- linkers include N-succinimidyl-4-(2-pyridylthio) butanoate eral sensory neuropathy (8%). Most of these AEs are man- (SPDB) and N-succinimidyl-4-(2-pyridyldithio) pentanoate ageable with dose reductions and/or delays [8, 53]. At the (SPP) [39]. 5-year follow-up, the overall survival (OS) and progression- Non-cleavable linkers are more stable but rely on free survival (PFS) rate for all patients were 41% and 22% complete proteolytic degradation of the whole mAb respectively.
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