Preclinical Evaluation of IMGC936, a Next-Generation Maytansinoid-based Antibody–drug Conjugate Targeting ADAM9-expressing Tumors

Scribner, Juniper A.; Hicks, Stuart W.; Sinkevicius, Kerstin W.; Yoder, Nicholas C.; Diedrich, Gundo; Brown, Jennifer G.; Lucas, Jacquelynn; Fuller, Megan E.; Son, Thomas; Dastur, Anahita; Hooley, Jeff; Espelin, Christopher W.; Themeles, Marian; Chen, Francine Z.; Li, Ying; Chiechi, Michael; Lee, Jenny; Barat, Bhaswati; Widjaja, Lusiana; Gorlatov, Sergey; Tamura, James; Ciccarone, Valentina; Ab, Olga; McEachem, Kerry A.; Koenig, Scott; Westin, Eric H.; Moore, Paul A.; Chittenden, Thomas; Gregory, Richard J.; Bonvini, Ezio; Loo, Deryk

doi:10.1158/1535-7163.mct-21-0915

Cited by 7 publications

(4 citation statements)

References 49 publications

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“…Recently, other than YTE and LS mutations, several mutations to increase FcRn binding have been reported and evaluated in preclinical and clinical studies [29][30][31]. Also, YTE mutations were reported to be applied in ADC [32] and Fc-fusion protein [33] to prolong half-life. The optimized allometric scaling approach could be widely used for mAbs and other therapeutic modalities which contain mutations to increase FcRn binding and can contribute to the efficient development of such therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Translational Approach for Predicting Human Pharmacokinetics of Engineered Therapeutic Monoclonal Antibodies with Increased FcRn-Binding Mutations

Haraya¹,

Tachibana²

2022

BioDrugs

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Introduction Recently, increasing FcRn binding by Fc engineering has become a promising approach for prolonging the half-life of therapeutic monoclonal antibodies (mAbs). This study is the first to investigate the optimization of an allometric scaling approach for engineered mAbs based on cynomolgus monkey data to predict human pharmacokinetics. Methods Linear two-compartmental model parameters (clearance [CL]; volume of distribution in the central compartment [ V c ]; inter-compartmental clearance [ Q ]; volume of distribution in the peripheral compartment [ V p ]) after the intravenous (IV) injection of engineered mAbs (M252Y/S254T/T256E or M428L/N434S mutations) in cynomolgus monkeys and humans were collected from published data. We explored the optimal exponent for allometric scaling to predict parameters in humans based on cynomolgus monkey data. Moreover, the plasma concentration–time profile of engineered mAbs after IV injection in humans was predicted using parameters estimated based on an optimized exponent. Results For engineered mAbs, a significant positive correlation between cynomolgus monkeys and humans was observed for CL, but not for other parameters. Whereas conventional exponents (CL: 0.8, Q : 0.75, V c : 1.0, V p : 0.95) previously established for normal mAbs showed poor prediction accuracy for CL and Q of engineered mAbs, the newly optimized exponents (CL: 0.55, Q : 0.6, V c : 0.95, V p : 0.95) achieved superior predictability for engineered mAbs. Moreover, the optimized exponents accurately predicted plasma mAb concentration–time profiles after IV injection of engineered mAbs in humans. Conclusions We found that engineered mAbs require specially optimized exponents to accurately predict pharmacokinetic parameters and plasma concentration–time profiles after IV injections in humans based on cynomolgus monkey data. This optimized approach can contribute to a more accurate prediction of human pharmacokinetics in the development of engineered mAbs.

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Section: Discussionmentioning

confidence: 99%

Translational Approach for Predicting Human Pharmacokinetics of Engineered Therapeutic Monoclonal Antibodies with Increased FcRn-Binding Mutations

Haraya¹,

Tachibana²

2022

BioDrugs

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“…As determined by a literature search of PubMed and ClinicalTrials.gov, two clinical trials targeting ADAMs are ongoing as of August 2022. The first is a first-in-human study of IMGC936 in patients with advanced solid tumors (NCT04622774) [ 115 ]. IMGC936 is a novel antibody–drug conjugate targeted against ADAM9 and comprises a high-affinity humanized antibody site.…”

Section: Adams As Immunotherapeutic Targetsmentioning

confidence: 99%

“…IMGC936 is a novel antibody–drug conjugate targeted against ADAM9 and comprises a high-affinity humanized antibody site. As preclinical data, Scribner et al reported that IMGC936 exhibits cytotoxicity in ADAM9-positive human tumor cell lines, along with bystander killing and potent antitumor activity in xenografts derived from tumors and human tumor cell lines [ 115 ]. A clinical trial combining an antibody-drug conjugate and immunotherapy is near at hand.…”

Section: Adams As Immunotherapeutic Targetsmentioning

confidence: 99%

The immunological role of ADAMs in the field of gastroenterological chronic inflammatory diseases and cancers: a review

et al. 2022

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Metalloproteinases cleave transmembrane proteins that play critical roles in inflammation and cancers. Metalloproteinases include a disintegrin and metalloprotease (ADAM), which we previously examined using a fluorescence assay system, and described their association with resistance to systemic therapy in cancer patients. There are also many reports on the relation between ADAM expression and the prognosis of patients with gastroenterological chronic inflammatory diseases and cancers. Inhibiting their immunomodulating activity in chronic inflammation restores innate immunity and potentially prevents the development of various cancers. Among the numerous critical immune system-related molecules, we focus on major histocompatibility complex class I polypeptide-related sequence A (MICA), MICB, intracellular adhesion molecule (ICAM)-1, TNF-α, IL-6 receptor (IL-6R), and Notch. This review summarizes our current understanding of the role of ADAMs in gastroenterological diseases with regard to the immune system. Several Food and Drug Administration (FDA)-approved inhibitors of ADAMs have been identified, and potential therapies for targeting ADAMs in the treatment of chronic inflammatory diseases and cancers are discussed. Some ongoing clinical trials for cancers targeting ADAMs are also introduced.

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“…A disintegrin and metalloproteinase domain-containing protein 9 (ADAM9) is a member of the ADAM family of transmembrane proteins belonging to the zinc protease superfamily. ADAM9 physiologically regulates cell adhesion and intracellular signal transduction in several malignant tumors [ 11 , 12 , 13 , 14 ]. In bladder and prostate cancers, knockdown of ADAM9 suppresses cancer cell proliferation [ 15 , 16 ] and inhibits cancer cell migration by suppressing epithelial–mesenchymal transition (EMT), which is related to cancer progression and metastasis [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

An Antibody of the Secreted Isoform of Disintegrin and Metalloprotease 9 (sADAM9) Inhibits Epithelial–Mesenchymal Transition and Migration of Prostate Cancer Cell Lines

Jotatsu,

Sung,

et al. 2024

IJMS

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Prostate cancer (PC) is the most common cancer diagnosed in men worldwide. Currently, castration-resistant prostate cancer (CRPC), which is resistant to androgen deprivation therapy, has a poor prognosis and is a therapeutic problem. We investigated the antitumor effects on PC of an antibody neutralizing secreted disintegrin and metalloproteinase domain-containing protein 9 (sADAM9), which is a blood-soluble form. We performed proliferation assays, wound healing assays, invasion assays, Western blot (WB), and an in vivo study in which a sADAM9 neutralizing antibody was administered intratumorally to PC-bearing mice. In invasion assays, the sADAM9 neutralizing antibody significantly inhibited invasion in all cell lines (TRAMP-C2: p = 0.00776, LNCaP: p = 0.000914, PC-3: p = 0.0327, and DU145: p = 0.0254). We examined epithelial–mesenchymal transition (EMT) markers, one of the metastatic mechanisms, in WB and showed downregulation of Slug in TRAMP-C2, LNCaP, and DU145 and upregulation of E-cadherin in TRAMP-C2 and PC-3 by sADAM9 neutralization. In mouse experiments, the sADAM9 neutralizing antibody significantly suppressed tumor growth compared to controls (1.68-fold in TRAMP-C2, 1.89-fold in LNCaP, and 2.67-fold in PC-3). These results suggested that the sADAM9 neutralizing antibody inhibits invasion, migration, and tumor growth in PC. Previous studies examined the anti-tumor effect of knockdown of total ADAM9 or sADAM9, but this study used the new technology of neutralizing antibodies for sADAM9. This may be novel because there was no animal study using a neutralizing antibody for sADAM9 to see the relationship between ADAM9 expression and prostate cancer.

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Preclinical Evaluation of IMGC936, a Next-Generation Maytansinoid-based Antibody–drug Conjugate Targeting ADAM9-expressing Tumors

Cited by 7 publications

References 49 publications

Translational Approach for Predicting Human Pharmacokinetics of Engineered Therapeutic Monoclonal Antibodies with Increased FcRn-Binding Mutations

Translational Approach for Predicting Human Pharmacokinetics of Engineered Therapeutic Monoclonal Antibodies with Increased FcRn-Binding Mutations

The immunological role of ADAMs in the field of gastroenterological chronic inflammatory diseases and cancers: a review

An Antibody of the Secreted Isoform of Disintegrin and Metalloprotease 9 (sADAM9) Inhibits Epithelial–Mesenchymal Transition and Migration of Prostate Cancer Cell Lines

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