Antibody–Drug Conjugates for Cancer Therapy

Parslow, Adam C.; Parakh, Sagun; Lee, Fook-Thean; Gan, Hui; Scott, Andrew M.

doi:10.3390/biomedicines4030014

Cited by 77 publications

(78 citation statements)

References 94 publications

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“…Grade 3 corneal opacity and punctate keratitis were reported as a serious AE and DLT in individuals treated at 5.0 and 7.0 mg/kg total body weight, respectively. Following the change to AIBW dosing, the visual and corneal abnormalities observed were generally mild (≤grade 2) and similar in nature to those reported for other DM4-conjugated antibodies [68]. Due to the lack of FRα expression in the eye, it is reasonable to conclude that these effects were off-target and independent of target antigen expression.…”

supporting

confidence: 66%

“…In this manner, ADCs couple the targeting and pharmacokinetic features of the antibody moiety with the additional cancer-killing impact of the cytotoxic payload [51]. Importantly, this unique method of site-selective drug delivery affords a means to reduce off-target toxicities in patients by limiting the exposure of normal tissues to the payload [52]. Clearly, appropriate antigen selection is critical for the ultimate activity and tolerability of ADC-based treatment modalities.…”

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confidence: 99%

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A Review of Mirvetuximab Soravtansine in the Treatment of Platinum-Resistant Ovarian Cancer

et al. 2017

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Resistance to platinum-based therapy poses a significant clinical challenge for the management of advanced ovarian cancer, a leading cause of cancer mortality among women. Mirvetuximab soravtansine is a novel antibody-drug conjugate that targets folate receptor-α, a validated molecular target for therapeutic intervention in this disease. Here, we examine mirvetuximab soravtansine's mechanism of action and pharmacology, and review its clinical evaluation in ovarian cancer to date. We focus on the favorable tolerability and encouraging signals of efficacy that have emerged, most notably in patients with platinum-resistant disease. Ongoing Phase III monotherapy and Phase Ib/II combination trials evaluating its activity in the setting of platinum resistance are emphasized, which will help define its role in the evolving landscape of ovarian cancer therapy. Ovarian cancer landscapeOvarian cancer remains a leading cause of gynecological cancer mortality, responsible for 152,000 deaths annually worldwide [1]. In the USA alone, it is estimated that 22,440 women will be diagnosed with ovarian cancer in 2017 and more than 14,000 will die due to this disease [2]. The remarkable degree of cellular and molecular heterogeneity exhibited by tumors of the ovary (including those arising from the fallopian tubes and primary peritoneum) is such that ovarian cancer is no longer considered a single disease entity with variable morphology, but rather a collection of neoplasms each associated with their own distinct histological subtypes and response to therapy [3,4]. Among these, epithelial ovarian cancer (EOC) accounts for approximately 95% of ovarian cancer malignancies [5,6]. The foundation of current standard-of-care treatment for women diagnosed with EOC is cytoreductive (debulking) surgery and chemotherapy using a platinum-based combination regimen, most commonly the carboplatin-paclitaxel doublet. This strategy has largely reached a plateau of effectiveness in improving overall patient survival [7,8]. The continuing high mortality is associated, at least in part, with the fact that EOC is overwhelmingly diagnosed at an advanced stage. Furthermore, while EOC is highly chemosensitive and most individuals achieve remission with front-line therapy, up to 80% of patients relapse and require further treatment without the expectation of cure [9].The development of platinum resistance in EOC appears to be a dynamic and multifactorial process, although the underlying molecular mechanisms remain poorly defined [10,11]. Recurrent EOC is classified based on the length Drug Evaluation Moore, Martin, O'Malley et al. of time, empirically divided into 6-month blocks, since receiving treatment with a platinum agent, known as the platinum-free interval [7,12]. The classification is as follows:r Refractory: progression during or within 4 weeks of platinum-based chemotherapy; r Primary resistant: relapse within 6 months of completing initial platinum therapy; r Partially platinum sensitive: relapse between 6 and 12 months; r Platinum sensitiv...

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confidence: 66%

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confidence: 99%

A Review of Mirvetuximab Soravtansine in the Treatment of Platinum-Resistant Ovarian Cancer

et al. 2017

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“…An ideal ADC combines the unique ability of an antibody to specifically bind a tumor-associated antigen that is minimally or in best case not expressed on healthy cells, a biodegradable linker that is stable in circulation, and the potent activity of a cytotoxic reagent such as a small-molecule drug 1,2. The first cytotoxic reagents in ADCs included the drugs doxorubicin and 5-fluorouracil, but these have been replaced more recently with two major classes of reagents with subnanomolar intracellular cytotoxicity, namely DNA-damaging drugs and microtubule inhibitors 1,3,4. Most of the cytotoxic ADC components in preclinical/clinical development are inhibitors of tubulin polymerization, including the maytansinoids (DM1/DM4) and monomethyl auristatin analogs E and F (MMAE/MMAF).…”

Section: Introductionmentioning

confidence: 99%

“…Most of the cytotoxic ADC components in preclinical/clinical development are inhibitors of tubulin polymerization, including the maytansinoids (DM1/DM4) and monomethyl auristatin analogs E and F (MMAE/MMAF). They inhibit cell division by binding to tubulin, which blocks tubulin assembly, arrests the target cells in the G2/M phase of the cell cycle, and ultimately induces apoptosis 3,5. MMAE and MMAF are synthetic analogs of the antimitotic natural product dolastatin 10 from the sea hare Dolabella auricularia 4.…”

Section: Introductionmentioning

confidence: 99%

Comparison of a mouse and a novel human scFv-SNAP-auristatin F drug conjugate with potent activity against EGFR-overexpressing human solid tumor cells

Woitok¹,

Klose²,

Fiore³

et al. 2017

OTT

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Antibody–drug conjugates (ADCs) can deliver toxins to specific targets such as tumor cells. They have shown promise in preclinical/clinical development but feature stoichiometrically undefined chemical linkages, and those based on full-size antibodies achieve only limited tumor penetration. SNAP-tag technology can overcome these challenges by conjugating benzylguanine-modified toxins to single-chain fragment variables (scFvs) with 1:1 stoichiometry while preserving antigen binding. Two (human and mouse) scFv-SNAP fusion proteins recognizing the epidermal growth factor receptor (EGFR) were expressed in HEK 293T cells. The purified fusion proteins were conjugated to auristatin F (AURIF). Binding activity was confirmed by flow cytometry/immunohistochemistry, and cytotoxic activity was confirmed by cell viability/apoptosis and cell cycle arrest assays, and a novel microtubule dynamics disassembly assay was performed. Both ADCs bound specifically to their target cells in vitro and ex vivo, indicating that the binding activity of the scFv-SNAP fusions was unaffected by conjugation to AURIF. Cytotoxic assays confirmed that the ADCs induced apoptosis and cell cycle arrest at nanomolar concentrations and microtubule disassembly. The SNAP-tag technology provides a platform for the development of novel ADCs with defined conjugation sites and stoichiometry. We achieved the stable and efficient linkage of AURIF to human or murine scFvs using the SNAP-tag technology, offering a strategy to improve the development of personalized medicines.

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“…Accordingly, ADCs couple the targeting and pharmacokinetic features of the antibody moiety with the additional cancer-killing impact of the payload [26]. This method of site-selective drug delivery affords a mechanism to reduce off-target toxicities in patients by limiting the exposure of normal tissues to the payload [27]. Currently there are four ADCs approved for cancer treatment: brentuximab vedotin (a conjugate of an anti-CD30 antibody with monomethyl auristatin E), ado-trastuzumab emtansine (T-DM1, a conjugate of the anti-HER2 antibody trastuzumab with the maytansinoid compound DM1), inotuzumab ozogamicin and gemtuzumab ozogamicin (conjugates of CD22-and CD33-targeting antibodies, respectively, with calicheamicin) [28].…”

mentioning

confidence: 99%

FORWARD I: A Phase III Study of Mirvetuximab Soravtansine Versus Chemotherapy in Platinum-Resistant Ovarian Cancer

Moore

Vergote²,

Oaknin

et al. 2018

Future Oncol.

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Mirvetuximab soravtansine, an antibody-drug conjugate that binds with high affinity to folate receptor-α to provide tumor-directed delivery of the potent microtubule-disrupting agent DM4, has emerged as a promising investigational agent for the treatment of ovarian cancer, particularly in the setting of platinum-resistant disease. Here we describe the rationale and design of FORWARD I (NCT02631876), the first randomized, multicenter Phase III study to compare the safety and efficacy of mirvetuximab soravtansine versus investigator's choice of chemotherapy in women with folate receptor-α-positive, platinumresistant epithelial ovarian, primary peritoneal or fallopian tube cancer. Patients will be randomized in a 2:1 ratio. The primary end point is progression-free survival, and key secondary objectives include comparison of overall response rates, overall survival and duration of response. Ovarian cancer is a leading cause of gynecologic cancer mortality worldwide, responsible for over 150,000 deaths each year [1]. Family history and the presence of penetrant mutations in genes such as BRCA1 and BRCA2 are significant risk factors for the development of ovarian cancer; epidemiological research has also identified a variety of hormonal and reproductive factors that can either increase (e.g., older age at menopause, hormone replacement therapy) or decrease (e.g., parity, lactation, oral contraceptive use) the likelihood of disease (reviewed in [2]). Epithelial ovarian cancer (EOC) accounts for approximately 95% of ovarian cancer malignancies [3,4]. EOC is highly chemosensitive, with the current standard-of-care treatment for newly diagnosed cases involving debulking surgery and adjuvant platinum-and taxane-based combination chemotherapy. Most individuals achieve remission with front-line therapy; unfortunately up to 80% of patients will relapse during or after treatment with eventual drug-resistant disease [5]. Disease recurring within 6 months of platinum-based chemotherapy is classified as platinum-resistant, whereas disease recurring >6 months after therapy is considered platinum sensitive. Patients with platinum-sensitive disease have a high likelihood of responding to additional platinum-based therapy; however, almost all will eventually develop acquired (secondary) platinum resistance [5,6] ovarian cancer typically receive single-agent chemotherapy at relapse. Outcomes for these patients remain poor, with low response rates to further chemotherapy (15-20%), progression-free survival (PFS) of 3-4 months [7][8][9], and a median overall survival rate of less than a year [5]. In addition, this treatment approach is associated with additional, cumulative toxicities and limited tolerability for patients. It has been suggested that natural compounds, such as phytochemicals, may alleviate chemotherapy-induced side effects and therefore may be useful as adjuvants to standard treatment [10]; however, this field remains in its infancy. These measures underscore a critical need for innovative and effective therapeutic stra...

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Antibody–Drug Conjugates for Cancer Therapy

Cited by 77 publications

References 94 publications

A Review of Mirvetuximab Soravtansine in the Treatment of Platinum-Resistant Ovarian Cancer

A Review of Mirvetuximab Soravtansine in the Treatment of Platinum-Resistant Ovarian Cancer

Comparison of a mouse and a novel human scFv-SNAP-auristatin F drug conjugate with potent activity against EGFR-overexpressing human solid tumor cells

FORWARD I: A Phase III Study of Mirvetuximab Soravtansine Versus Chemotherapy in Platinum-Resistant Ovarian Cancer

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