222 A first-in-human, phase I trial of the anti-DLL4 antibody (OMP-21M18) targeting cancer stem cells (CSC) in patients with advanced solid tumors

Smith, David C.; Eisenberg, Paul R.; Stagg, Robert; Manikhas, G.; Pavlovskiy, A. V.; Šikić, Branimir I.; Kapoun, Ann M.; Benner, Steven E.

doi:10.1016/s1359-6349(10)71927-3

Cited by 7 publications

(7 citation statements)

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“…The well-established role of DLL4/NOTCH1 in tumor angiogenesis and the potent efficacy associated with pathway inhibition across numerous preclinical tumor models has advanced several DLL4 neutralizing antibodies (OMP-21M18, REGN421, and MEDI0639) into clinical studies in various solid tumor settings (22,32). We previously reported that chronic administration of a full-length anti-DLL4 IgG1 antibody was associated with induction of vascular neoplasms in rats as well as pathologic changes in the liver in rats and monkeys (23).…”

Section: Discussionmentioning

confidence: 99%

“…For instance, with respect to changes in the cardiopulmonary system, an anti-DLL4 antibody (MEDI0639) also evaluated in monkeys was associated with pathologic changes in the heart and lung, as indicated by elevations in blood pressure, heart rate, and C-reactive protein, and observations of heart failure (37). In humans, another anti-DLL4 antibody (OMP-21M18) has been associated with grade III asymptomatic hypertension in approximately 28% of phase I patients (22). In addition, an anti-DLL4 antibody (REGN421) reported hypertension as well as grade II and III pulmonary hypertension in 14% of patients in a phase I trial (38).…”

Section: Discussionmentioning

confidence: 99%

“…via the tail vein at 0 (vehicle), 3, 10, 30, or 100 mg/kg/week (total dose level) on a 2 on/5 off dosing schedule over 8 weeks (e.g., Days 1,2,8,9,15,16,22,23,29,30,36,37,43,44, 50, 51, 57, and 58; 18 total doses). Vehicle consisted of 20 mmol/L Na 2 succinate, 240 mmol/L sucrose, 0.02% polysorbate 20, at pH 5.5.…”

Section: Translational Relevancementioning

confidence: 99%

“…Finally, although vascular neoplasms were not observed in monkeys, dose-dependent, moderate-to-severe acute hemolytic anemia occurred in some animals, leading to mortality in the most severe cases. Clinical trials of the DLL4-targeting antibody OMP-21M18 have also revealed safety concerns in humans, including grade III asymptomatic hypertension, that were not noted in published preclinical studies (22).…”

Section: Introductionmentioning

confidence: 99%

“…In addition to the potent antitumor activity observed following anti-DLL4 treatment, additive antitumor activity has also been observed in combination with anti-VEGF therapy and/or chemotherapy (14,(16)(17)(18)21). Based on the important role of DLL4 in vascular biology as well as the broad preclinical antitumor activity of anti-DLL4 monoclonal antibodies, several anti-DLL4 molecules are currently being investigated in clinical trials as potential cancer therapeutics (22).…”

Section: Introductionmentioning

confidence: 99%

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Balancing Efficacy and Safety of an Anti-DLL4 Antibody through Pharmacokinetic Modulation

Couch

Z²,

Beyer

et al. 2016

Clinical Cancer Research

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Purpose: Although agents targeting Delta-like ligand 4 (DLL4) have shown great promise for angiogenesis-based cancer therapy, findings in recent studies have raised serious safety concerns. To further evaluate the potential for therapeutic targeting of the DLL4 pathway, we pursued a novel strategy to reduce toxicities related to DLL4 inhibition by modulating the pharmacokinetic (PK) properties of an anti-DLL4 antibody.Experimental Design: The F(ab 0 ) 2 fragment of anti-DLL4 antibody (anti-DLL4 F(ab 0 ) 2 ) was generated and assessed in efficacy and toxicity studies.Results: Anti-DLL4 F(ab 0 ) 2 enables greater control over the extent and duration of DLL4 inhibition, such that intermittent dosing of anti-DLL4 F(ab 0 ) 2 can maintain significant antitumor activity while markedly mitigating known toxicities associated with continuous pathway inhibition.Conclusions: PK modulation has potentially broad implications for development of antibody-based therapeutics. Our safety studies with anti-DLL4 F(ab 0 ) 2 also provide new evidence reinforcing the notion that the DLL4 pathway is extremely sensitive to pharmacologic perturbation, further underscoring the importance of exercising caution to safely harness this potent pathway in humans.

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Section: Discussionmentioning

confidence: 99%