A Phase I, Multicenter, Open-label Dose Escalation and Expansion Study of LOP628, Administered Intravenously in Adult Patients With cKit-positive Tumors and Acute Myeloid Leukemia

LOP628 is an antibody-drug conjugate (ADC) consisting of an anti-cKit humanized IgG1/κ antibody conjugated to a maytansine payload via a non-cleavable linker.
LOP628 provides an opportunity to target cKit overexpressing tumors.

Start Date01 Dec 2014

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

100 Clinical Results associated with Anti-c-kit humanised IgG1/κ antibody-maitansine conjugate(Novartis Pharma AG)

100 Translational Medicine associated with Anti-c-kit humanised IgG1/κ antibody-maitansine conjugate(Novartis Pharma AG)

100 Patents (Medical) associated with Anti-c-kit humanised IgG1/κ antibody-maitansine conjugate(Novartis Pharma AG)

Literatures (Medical) associated with Anti-c-kit humanised IgG1/κ antibody-maitansine conjugate(Novartis Pharma AG)

01 Sep 2018·Clinical Cancer ResearchQ1 · MEDICINE

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

Q1 · MEDICINE

Article

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

AbstractPurpose: c-KIT overexpression is well recognized in cancers such as gastrointestinal stromal tumors (GIST), small cell lung cancer (SCLC), melanoma, non–small cell lung cancer (NSCLC), and acute myelogenous leukemia (AML). Treatment with the small-molecule inhibitors imatinib, sunitinib, and regorafenib resulted in resistance (c-KIT mutant tumors) or limited activity (c-KIT wild-type tumors). We selected an anti–c-KIT ADC approach to evaluate the anticancer activity in multiple disease models.Experimental Design: A humanized anti–c-KIT antibody LMJ729 was conjugated to the microtubule destabilizing maytansinoid, DM1, via a noncleavable linker (SMCC). The activity of the resulting ADC, LOP628, was evaluated in vitro against GIST, SCLC, and AML models and in vivo against GIST and SCLC models.Results: LOP628 exhibited potent antiproliferative activity on c-KIT–positive cell lines, whereas LMJ729 displayed little to no effect. At exposures predicted to be clinically achievable, LOP628 demonstrated single administration regressions or stasis in GIST and SCLC xenograft models in mice. LOP628 also displayed superior efficacy in an imatinib-resistant GIST model. Further, LOP628 was well tolerated in monkeys with an adequate therapeutic index several fold above efficacious exposures. Safety findings were consistent with the pharmacodynamic effect of neutropenia due to c-KIT–directed targeting. Additional toxicities were considered off-target and were consistent with DM1, such as effects in the liver and hematopoietic/lymphatic system.Conclusions: The preclinical findings suggest that the c-KIT–directed ADC may be a promising therapeutic for the treatment of mutant and wild-type c-KIT–positive cancers and supported the clinical evaluation of LOP628 in GIST, AML, and SCLC patients. Clin Cancer Res; 24(17); 4297–308. ©2018 AACR.

15 Jul 2018·Clinical Cancer ResearchQ1 · MEDICINE

Mechanistic Insights of an Immunological Adverse Event Induced by an Anti-KIT Antibody Drug Conjugate and Mitigation Strategies

Q1 · MEDICINE

Article

Author: L'Italien, Lawrence ; Lee-Hoeflich, Si Tuen ; Ebersbach, Hilmar ; Abrams, Tinya ; Connor, Anu ; Desai, Jayesh ; Cantagallo, Lisa ; Orozco, Olivia ; Skegro, Darko ; Maacke, Heiko ; Lees, Emma ; Gelderblom, Hans ; Schleyer, Siew ; Hoffmaster, Keith

AbstractPurpose: Hypersensitivity reactions (HSRs) were observed in three patients dosed in a phase I clinical trial treated with LOP628, a KIT targeted antibody drug conjugate. Mast cell degranulation was implicated as the root cause for the HSR. Underlying mechanism of this reported HSR was investigated with an aim to identifying potential mitigation strategies.Experimental Design: Biomarkers for mast cell degranulation were evaluated in patient samples and in human peripheral blood cell-derived mast cell (PBC-MC) cultures treated with LOP628. Mitigation strategies interrogated include pretreatment of mast cells with small molecule inhibitors that target KIT or signaling pathways downstream of FcϵR1, FcγR, and treatment with Fc silencing antibody formats.Results: Transient elevation of serum tryptase was observed in patients 1-hour posttreatment of LOP628. In agreement with the clinical observation, LOP628 and its parental antibody LMJ729 induced degranulation of human PBC-MCs. Unexpectedly, KIT small molecule inhibitors did not abrogate mast cell degranulation. By contrast, small molecule inhibitors that targeted pathways downstream of Fc receptors blunted degranulation. Furthermore, interference of the KIT antibody to engage Fc receptors by pre-incubation with IgG or using engineered Fc silencing mutations reduced or prevented degranulation. Characterization of Fcγ receptors revealed human PBC-MCs expressed both FcγRII and low levels of FcγRI. Interestingly, increasing the level of FcγRI upon addition of IFNγ, significantly enhanced LOP628-mediated mast cell degranulation.Conclusions: Our data suggest LOP628-mediated mast cell degranulation is the likely cause of HSR observed in the clinic due to co-engagement of the FcγR and KIT, resulting in mast cell activation. Clin Cancer Res; 24(14); 3465–74. ©2018 AACR.

100 Deals associated with Anti-c-kit humanised IgG1/κ antibody-maitansine conjugate(Novartis Pharma AG)

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Phase 1	NL	Novartis Pharmaceuticals Corp.	01 Dec 2014
Acute Myeloid Leukemia	Phase 1	BE	Novartis Pharmaceuticals Corp.	01 Dec 2014
Acute Myeloid Leukemia	Phase 1	AU	Novartis Pharmaceuticals Corp.	01 Dec 2014
Acute Myeloid Leukemia	Phase 1	ES	Novartis Pharmaceuticals Corp.	01 Dec 2014
LTK-positive Solid Tumors	Phase 1	NL	Novartis Pharmaceuticals Corp.	01 Dec 2014
LTK-positive Solid Tumors	Phase 1	AU	Novartis Pharmaceuticals Corp.	01 Dec 2014
LTK-positive Solid Tumors	Phase 1	BE	Novartis Pharmaceuticals Corp.	01 Dec 2014
LTK-positive Solid Tumors	Phase 1	ES	Novartis Pharmaceuticals Corp.	01 Dec 2014

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