Preclinical Antitumor Activity of a Novel Anti–c-KIT Antibody–Drug Conjugate against Mutant and Wild-type c-KIT–Positive Solid Tumors

Abrams, Tinya J.; Connor, Anu; Fanton, Christie; Cohen, Steven B.; Huber, Thomas; Miller, Kathy; Hong, Erica; Niu, Xiaohong; Kline, Janine; Ison-Dugenny, Marjorie; Harris, Sarah; Walker, Dana B; Krauser, Klaus; Galimi, Francesco; Wang, Zhen; Ghoddusi, Majid; Mansfield, Keith G.; Lee-Hoeflich, Si Tuen; Holash, Jocelyn; Pryer, Nancy; Kluwe, William M.; Ettenberg, Seth A.; Sellers, William R.; Lees, Emma; Kwon, Paul; Abraham, Judith A.; Schleyer, Siew

doi:10.1158/1078-0432.ccr-17-3795

Cited by 46 publications

(46 citation statements)

References 27 publications

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“…Our approach complements other methods for targeting SCF for therapeutic application. A recent example of that type of study was presented by a group from Novartis [ 50 ] demonstrating the potency of a c-KIT-directed ADC (a humanized anti-c-KIT antibody conjugated to a microtubule destabilizing small molecule) in models of mutant and wild-type c-KIT-positive solid tumors. In this respect, the significance of our study stems from the insight it provides into the sequence-structure–function relationships and mechanism of action of agonistic and antagonistic SCF mutants and it will therefore support engineering of further improved SCF variants as potential therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Engineering Stem Cell Factor Ligands with Different c-Kit Agonistic Potencies

et al. 2020

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Receptor tyrosine kinases (RTKs) are major players in signal transduction, regulating cellular activities in both normal regeneration and malignancy. Thus, many RTKs, c-Kit among them, play key roles in the function of both normal and neoplastic cells, and as such constitute attractive targets for therapeutic intervention. We thus sought to manipulate the self-association of stem cell factor (SCF), the cognate ligand of c-Kit, and hence its suboptimal affinity and activation potency for c-Kit. To this end, we used directed evolution to engineer SCF variants having different c-Kit activation potencies. Our yeast-displayed SCF mutant (SCFM) library screens identified altered dimerization potential and increased affinity for c-Kit by specific SCF-variants. We demonstrated the delicate balance between SCF homo-dimerization, c-Kit binding, and agonistic potencies by structural studies, in vitro binding assays and a functional angiogenesis assay. Importantly, our findings showed that a monomeric SCF variant exhibited superior agonistic potency vs. the wild-type SCF protein and vs. other high-affinity dimeric SCF variants. Our data showed that action of the monomeric ligands in binding to the RTK monomers and inducing receptor dimerization and hence activation was superior to that of the wild-type dimeric ligand, which has a higher affinity to RTK dimers but a lower activation potential. The findings of this study on the binding and c-Kit activation of engineered SCF variants thus provides insights into the structure–function dynamics of ligands and RTKs.

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Section: Discussionmentioning

confidence: 99%

Engineering Stem Cell Factor Ligands with Different c-Kit Agonistic Potencies

et al. 2020

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“…These observations indicate that cancer‐derived EVs can transfer their contents into tumour stromal cells (Peinado et al., 2017). Tisotumab vedotin, an ADC targeting tissue factor (De Bono et al., 2019), and several ADCs against EGFR are currently being investigated in clinical trials, while the clinical development of an anti‐KIT ADC and an anti‐integrin αv ADC (LOP628 (Abrams et al., 2018) and IMGN388 (Bendell et al., 2010; Raab‐Westphal et al., 2017), respectively) has been discontinued (Supplementary Table 1).…”

Section: Influence Of Evs On the Efficacy Of Adcsmentioning

confidence: 99%

Extracellular vesicles as modifiers of antibody‐drug conjugate efficacy

Barok

Puhka

Yazdi

et al. 2021

J of Extracellular Vesicle

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Antibody‐drug conjugates (ADCs) are a new class of anti‐cancer drugs that consist of a monoclonal antibody, a highly potent small‐molecule cytotoxic drug, and a chemical linker between the two. ADCs can selectively deliver cytotoxic drugs to cancer cells leading to a reduced systemic exposure and a wider therapeutic window. To date, nine ADCs have received marketing approval, and over 100 are being investigated in nearly 600 clinical trials. The target antigens of at least eight out of the nine approved anti‐cancer ADCs and of 69 investigational ADCs are present on extracellular vesicles (EVs) (tiny particles produced by almost all types of cells) that may carry their contents into local and distant cells. Therefore, the EVs have a potential to mediate both the anti‐cancer effects and the adverse effects of ADCs. In this overview, we discuss the mechanisms of action of ADCs and the resistance mechanisms to them, the EV‐mediated resistance mechanisms to small molecule anti‐cancer drugs and anti‐cancer monoclonal antibodies, and the EVs as modifiers of ADC efficacy and safety.

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“…Five ADCs have been approved by the Food and Drug Administration: brentuximab vedotin for Hodgkin lymphoma [15], ado-trastuzumab emtansine for HER2positive metastatic breast cancer [16,17], inotuzumab ozogamicin for acute lymphoblastic leukemia [18], gemtuzumab ozogamicin for CD33-positive acute myeloid leukemia [19], and trastuzumab deruxtecan for unresectable or metastatic HER2-positive breast cancer patients who have received two or more prior anti-HER2based regimens in a metastatic setting [20]. To date, ADCs targeting solid tumors other than metastatic breast cancer have not exhibited distinct clinical benefits [21][22][23][24][25][26][27][28][29]. In SCLC, DLL3, a cell surface Notch ligand that appear to be a direct downstream target of ASCL1 [30,31], has been identified as a novel target for ADCs [32].…”

Section: Research Papermentioning

confidence: 99%

NRXN1 as a novel potential target of antibody-drug conjugates for small cell lung cancer

et al. 2020

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Small cell lung cancer (SCLC) is a high-grade malignancy, and treatment strategies have not changed for decades. In this study, we searched for novel targets for antibody-drug conjugate (ADC) therapy for SCLC. We identified transmembrane proteins overexpressed specifically in SCLC with little or no expression in normal tissues and decided to focus on the cell adhesion molecule neurexin-1 (NRXN1). The cell surface overexpression of NRXN1 was confirmed using flow cytometry in SCLC cell lines (SHP77 and NCI-H526). The combination of a primary anti-NRXN1 monoclonal antibody and a secondary ADC exhibited anti-tumor activity in SCLC cell lines. Moreover, the knockout of NRXN1 in SHP77 cells resulted in a loss of the antitumor activity of NRXN1-mediated ADC therapy. Thus, NRXN1 could be a novel target for ADC therapy for the treatment of SCLC that is worth further research.

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Preclinical Antitumor Activity of a Novel Anti–c-KIT Antibody–Drug Conjugate against Mutant and Wild-type c-KIT–Positive Solid Tumors

Cited by 46 publications

References 27 publications

Engineering Stem Cell Factor Ligands with Different c-Kit Agonistic Potencies

Engineering Stem Cell Factor Ligands with Different c-Kit Agonistic Potencies

Extracellular vesicles as modifiers of antibody‐drug conjugate efficacy

NRXN1 as a novel potential target of antibody-drug conjugates for small cell lung cancer

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