Antibody Drug Conjugates: Progress, Pitfalls, and Promises
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Human Antibodies 27 (2019) 53–62 53 DOI 10.3233/HAB-180348 IOS Press Antibody drug conjugates: Progress, pitfalls, and promises Anubhab Mukherjeea;b, Ariana K. Watersa;b, Ivan Babicb, Elmar Nurmemmedovb, Mark C. Glassyc;d, Santosh Kesarib and Venkata Mahidhar Yenugondaa;b;∗ aDrug Discovery and Nanomedicine Research Program, CA-90404, USA bDepartment of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Pacific Neuroscience Institute, Providence Saint John’s Health Center, Santa Monica, CA-90404, USA cUniversity of California San Diego, Moores Cancer Center, La Jolla, CA, USA dNascent Biotech, Inc., San Diego, CA, USA Abstract. Antibody drug conjugates (ADCs) represent a promising and an efficient strategy for targeted cancer therapy. Com- prised of a monoclonal antibody, a cytotoxic drug, and a linker, ADCs offer tumor selectively, reduced toxicity, and improved stability in systemic circulation. Recent approvals of two ADCs have led to a resurgence in ADC research, with more than 60 ADCs under various stages of clinical development. The therapeutic success of future ADCs is dependent on adherence to key requirements of their design and careful selection of the target antigen on cancer cells. Here we review the main components in the design of antibody drug conjugates, improvements made, and lessons learned over two decades of research, as well as the future of third generation ADCs. Keywords: Monoclonal antibodies, target antigens, linker, cytotoxic drugs, site-specific drug conjugation, antibody-drug conju- gates 1. Introduction lin targeting molecules (Taxanes, Vinca alkaloids) sub- sequently came into play. The triumph of eliminat- For several decades, chemotherapy has remained ing cancer cells was unfortunately retarded by a lack the preeminent modality for the treatment of can- of tumor selectivity, in which chemotherapy ended up cer [1,2]. The earliest category of chemotherapeutics killing normal cells, eventually leading to unforeseen tested in humans were chlorambucil and cyclophos- systemic toxicities. However, it was soon discerned phamide, which were reported to induce cellular cyto- that therapeutics with non-overlapping toxicity pro- toxicity by DNA alkylation. The recognition that folic files and different mechanisms of action could be com- acid stimulates cancer cell growth led to the synthe- bined at different dose regimen to yield synergistic sis of antifolates, such as methotrexate, as antitumor antitumor activity. Combinatorial chemotherapy thus agents. This was followed by nucleoside analogues, emerged as a modality for the treatment of most can- such as 5-fluoruracil, and cytosine arabinoside (ara- cers [3]. Clinicians worked with a plethora of individ- C), which essentially interfere with DNA synthesis. ual drugs and their combinations to define the maxi- DNA inter-chelating agents such as cisplatin, actino- mum tolerated dose (MTD), minimum effective dose mycin D, anthracyclines (e.g., Doxorubicin) and tubu- (MED) and later, metronomic dose (MET) in order to reach an improved therapeutic index. In more recent decades, an increased understand- ∗Corresponding author: Venkata Mahidhar Yenugonda, Drug Dis- ing of cancer biology has spawned a new era of tar- covery and Nanomedicine Research Program, John Wayne Can- geted cancer treatment by exploiting certain properties cer Institute, Pacific Neuroscience Institute, Providence Saint John’s Health Center, Santa Monica, CA-90404, USA. Tel.: +1 310 582 of tumor cells in contrast to normal cells [4]. These 7489; E-mail: [email protected]. salient features, popularly coined the ‘hallmarks of ISSN 1093-2607/19/$35.00 c 2019 – IOS Press and the authors. All rights reserved 54 A. Mukherjee et al. / Antibody drug conjugates Fig. 1. Antibody Drug Conjugate. (A) General depiction of the structure of an antibody drug conjugate (ADC). The cytotoxic payload is con- jugated via variable types of linkers to a human, humanized, or hybrid monoclonal antibody (mAb). The antigen binding region of the mAb is indicated in light green. (B) Mechanism of action of ADCs. The circulating ADCs binds to cancer specific antigens and gets internalized through receptor mediated endocytosis (RME). Once internalized, the linker is either cleaved by a change from the bloodstream to the cellular environ- ment, or by active degradation by lysosomes. The cytotoxic compound then diffuses through the cytoplasm to disrupt microtubule assembly or into the nucleus to induce DNA damage, finally resulting in cell apoptosis. cancer’ by Robert Weinberg and Douglas Hanahan, en- specific mAb conjugated to a potent cytotoxin via a able tumor cells to survive, multiply, and metastasize ‘stable’ linker (Fig.1). In this review we summarize by altering several cellular mechanics, which include: clinical advancements, challenges and future perspec- attaining an autonomy in growth signals, insensitiv- tives in the development of ADCs. ity to anti-growth signals, evasion of apoptosis, infi- nite replicative potential, sustained angiogenesis, tis- sue invasion and metastasis, reprogramming cellular 2. Bench-side to bedside journey metabolism and evasion of immunological destruction. Targeted therapy of the ‘hallmarks of cancer’ promises ADCs are one of the most intricate drug delivery selective cytotoxicity to the tumor cells, which ensures platforms in the existing range of oncology medica- overall lower toxicity to the patient and yields a higher tions. They are immuno-conjugates composed of re- therapeutic index compared to traditional chemother- combinant monoclonal antibodies (mAbs), grafted to a apy. small molecule cytotoxic agent via covalent linker [8]. Cancer cells differ from normal cells due to genomic However, some major concerns impeding their clinical instability causing mutations in oncogenes and/or tu- success, namely: (i) the expression of the target anti- mor suppressor genes [5]. Once the integrity of the gen on the tumor versus normal tissues, (ii) the rate of genome is compromised, cells are more likely to de- internalization of the payload, (iii) the selection of pay- velop additional genetic faults; some of which may load for the tumor indication, and (iv) the linker stabil- give rise to tumor-specific antigens (found only on the ity and off-target toxicities [9]. It is therefore not sur- surface of tumor cells) or tumor-associated antigens prising that we have only few commercially available (overexpressed on tumor cells, but also present on nor- agents despite over one hundred clinical trials evaluat- mal cells) [6]. Ongoing research has demonstrated that ing this platform. several human cancers express unique tumor-specific The journey began with promising preclinical data or tumor-associated cell surface antigens, which are from a study demonstrating the antitumor effect of of great value as targets for monoclonal antibody BR96-doxorubicin on breast cancer xenografts, where (mAb)-based therapy [7]. Besides developing small doxorubicin was conjugated to an IgG1 antibody tar- and large molecule based receptor-mediated targeted geting the LewisY antigen and had a drug to anti- cancer therapy, enormous efforts have also been di- body ratio (DAR) of 4:1. However, an imbalance of rected towards developing an entirely new class of tri- ‘on-target’ toxicity between normal and tumor cells partite anti-cancer drugs, namely, antibody-drug con- ultimately led to its failure [10–12]. The first ADC jugates (ADCs). These drugs are comprised of a tumor- approved by the U.S. Food and Drug Administration Table 1 Leading antibody drug conjugates in the market and in clinical trials ADC name, (trade name) Target antigen Antibody Drug Linker Indication Company Current status Gemtuzumab ozagamicin CD33 Engineered huIgG4 N-acetyl-γ Cleavable Myelgenons leukemia Pfizer Approved 2001 (Mylotarg) calicheamicin hydrazone Withdrawn 2011 Brentuximab vedotin CD30 chIgG1 MMAE (auristatin) Cleavable Relasped Hodgkin Seattle/Millenium Approved 2011 (Adecetris) dipeptide (vc) lymphoma, systemic Takeda anaplastic large cell lymphoma A. Mukherjee et al. / Antibody drug conjugates Trastuzumab enutansine HER2 tastuzumab DM1 SMCC HER2 positive Genentech & Roche Approved 2013 (Kadcyla) metastatic breast cancer Inotuzumab ozogamicin CD22 Engineered huIgG4 N-acetyl-γ Cleavable Refractory BCell Pfizer Approved 2017 (Bespousa) calicheamicin hydrazone precursor ALL Vadastuximab talirine CD33 huIgG1 engineered for PBD dimer Cleavable Acute myeloid leukemia Seattle Genetics Phase III halted (SGN-CD33A) site-specific linking dipeptide (va) (AML) 2017 Glembatumumab vedotin Glycoprotein NMB Glembatumumab Fully vc-MMAE (auristatin) Cleavable Metastatic breast cancer Celldex Therapeutics Phase II (CR011-vcMMAE; (osteoactivin) human IgG1 dipeptide (MBC) and melanoma (Seattle Genetics CDX-011) ADC technology) Depatuxizumab Epidermal growth Depatuxizumabb mcMMAF (auristatin) Uncleavable EGFR-overexpressing Abbvie (Seattle Phase II mafodotin (ABT-414) factor receptor (ABT-806) Humanized maleimido- solid tumors, Genetics ADC (EGFR) IgG1 caproyl glioblastoma technology) Anetumab ravtansine Mesothelin huIgG1 (trastuzumab) DM4 (maytansinoid) Cleavable HER2-positive mBC Bayer Healthcare Phase IIb/II in (BAY 94-9343) disulfide (SPDB) comb. w/TMZ Rovalpituzumab tesirine Delta-like protein 3 Rovalpituzumab (SC16) Pyrrolobenzodiazepine Cleavable Small cell lung cancer Stemcentrx (now Phase III (SC16LD6.5; Rova-T) (DLL3) Humanized IgG1 (PBD) dimer dipeptide (SCLC) Abbvie) (Spirogen (valine-alanine) ADC technology) Mirvetuximab FOLR1 (folate