Pharmacokinetic Considerations for Antibody-Drug Conjugates against Cancer

Malik, Paul R. V.; Phipps, Colin; Edginton, Andrea N.; Blay, Jonathan

doi:10.1007/s11095-017-2259-3

Cited by 33 publications

(20 citation statements)

References 173 publications

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“…S1). Nonspecific binding as well as macrophage uptake, as previously observed with some mAbs (36,37), may also play a role in the observed accumulation in the spleen, in addition to possible aggregation/complexation. Variable accumulation of radioactivity in the spleen as a consequence of variable aggregation could possibly explain the non-dose-related lymphopenia observed.…”

Section: Discussionsupporting

confidence: 51%

Phase I Study of P-cadherin–targeted Radioimmunotherapy with 90Y-FF-21101 Monoclonal Antibody in Solid Tumors

Subbiah

Erwin

Mawlawi

et al. 2020

Clinical Cancer Research

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Purpose: 90 Y-FF-21101 is an Yttrium-90-conjugated, chimeric mAb that is highly specific for binding to human placental (P)cadherin, a cell-to-cell adhesion molecule overexpressed and associated with cancer invasion and metastatic dissemination in many cancer types. We report the clinical activity of 90 Y-FF-21101 in a firstin-human phase I study in patients with advanced solid tumors. Patients and Methods: The safety and efficacy of 90 Y-FF-21101 were evaluated in a phase I 3þ3 dose-escalation study in patients with advanced solid tumors (n ¼ 15) over a dose range of 5-25 mCi/m 2. Dosimetry using 111 In-FF-21101 was performed 1 week prior to assess radiation doses to critical organs. Patients who demonstrated clinical benefit received repeated 90 Y-FF-21101 administration every 4 months. Results: 111 In-FF-21101 uptake was observed primarily in the spleen, kidneys, testes, lungs, and liver, with tumor uptake observed in the majority of patients. Organ dose estimates for all patients were below applicable limits. P-cadherin expression H-scores ranged from 0 to 242 with 40% of samples exhibiting scores ≥100. FF-21101 protein pharmacokinetics were linear with increasing antibody dose, and the mean half-life was 69.7 (AE12.1) hours. Radioactivity clearance paralleled antibody clearance. A complete clinical response was observed in a patient with clear cell ovarian carcinoma, correlating with a high tumor P-cadherin expression. Stable disease was observed in a variety of other tumor types, without doselimiting toxicity. Conclusions: The favorable safety profile and initial antitumor activity observed for 90 Y-FF-21101 warrant further evaluation of this radioimmunotherapeutic (RIT) approach and provide initial clinical data supporting P-cadherin as a potential target for cancer treatment.

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Section: Discussionsupporting

confidence: 51%

Phase I Study of P-cadherin–targeted Radioimmunotherapy with 90Y-FF-21101 Monoclonal Antibody in Solid Tumors

Subbiah

Erwin

Mawlawi

et al. 2020

Clinical Cancer Research

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“…Significant overlap in the distribution of pola exposure exists, with the magnitude of differences being within the inter-individual variability of each analyte in the current study. These observations are not unexpected given the moderate inter-individual variability in exposure seen across other ADCs [46,47].…”

Section: Discussionmentioning

confidence: 68%

Pharmacokinetics of polatuzumab vedotin in combination with R/G-CHP in patients with B-cell non-Hodgkin lymphoma

Shemesh¹,

Agarwal²,

Tong³

et al. 2020

Cancer Chemother Pharmacol

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Purpose The phase Ib/II open-label study (NCT01992653) evaluated the antibody-drug conjugate polatuzumab vedotin (pola) plus rituximab/obinutuzumab, cyclophosphamide, doxorubicin, and prednisone (R/G-CHP) as first-line therapy for B-cell non-Hodgkin lymphoma (B-NHL). We report the pharmacokinetics (PK) and drug-drug interaction (DDI) for pola. Methods Six or eight cycles of pola 1.0-1.8 mg/kg were administered intravenously every 3 weeks (q3w) with R/G-CHP. Exposures of pola [including antibody-conjugated monomethyl auristatin E (acMMAE) and unconjugated MMAE] and R/G-CHP were assessed by non-compartmental analysis and/or descriptive statistics with cross-cycle comparisons to cycle 1 and/or after multiple cycles. Pola was evaluated as a potential victim and perpetrator of a PK drug-drug interaction with R/G-CHP. Population PK (popPK) analysis assessed the impact of prior treatment status (naïve vs. relapsed/refractory) on pola PK. Results Pola PK was similar between treatment arms and independent of line of therapy. Pola PK was dose proportional from 1.0 to 1.8 mg/kg with R/G-CHP. Geometric mean volume of distribution and clearance of acMMAE ranged from 57.3 to 95.6 mL/kg and 12.7 to 18.2 mL/kg/day, respectively. acMMAE exhibited multi-exponential decay (elimination half-life ~ 1 week). Unconjugated MMAE exhibited formation rate-limited kinetics.

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“…ADCs are large molecules (∼150 kDa) typically administered systemically by intravenous (IV) infusion ( Malik et al, 2017 ). After systemic administration, the distribution of the intact ADC is generally confined to the plasma, interstitial fluid, and lymph ( Han and Zhao, 2014 ).…”

Section: Occupational Exposure Control Banding Considerations For Phamentioning

confidence: 99%

“…After systemic administration, the distribution of the intact ADC is generally confined to the plasma, interstitial fluid, and lymph ( Han and Zhao, 2014 ). They often possess long plasma residence times because of their dynamic interactions with the FcRn ( Garg and Balthasar, 2007 ) and are therefore administered intermittently, typically once every 1–4 weeks ( Malik et al, 2017 ). In most, but not all cases, ADCs exhibit nonlinear PK and dose-dependent clearance due to saturable target binding and elimination ( Levy, 1994 ).…”

Section: Occupational Exposure Control Banding Considerations For Phamentioning

confidence: 99%

Considerations for setting occupational exposure limits for novel pharmaceutical modalities

Graham

Hillegass

Schulze

2020

Regulatory Toxicology and Pharmacology

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In order to develop new and effective medicines, pharmaceutical companies must be modality agnostic. As science reveals an enhanced understanding of biological processes, new therapeutic modalities are becoming important in developing breakthrough therapies to treat both rare and common diseases. As these new modalities progress, concern and uncertainty arise regarding their safe handling by the researchers developing them, employees manufacturing them and nurses administering them. This manuscript reviews the available literature for emerging modalities (including oligonucleotides, monoclonal antibodies, fusion proteins and bispecific antibodies, antibody-drug conjugates, peptides, vaccines, genetically modified organisms, and several others) and provides considerations for occupational health and safety-oriented hazard identification and risk assessments to enable timely, consistent and well-informed hazard identification, hazard communication and risk-management decisions. This manuscript also points out instances where historical exposure control banding systems may not be applicable (e.g. oncolytic viruses, biologics) and where other occupational exposure limit systems are more applicable (e.g. Biosafety Levels, Biologic Control Categories).

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Pharmacokinetic Considerations for Antibody-Drug Conjugates against Cancer

Cited by 33 publications

References 173 publications

Phase I Study of P-cadherin–targeted Radioimmunotherapy with 90Y-FF-21101 Monoclonal Antibody in Solid Tumors

Phase I Study of P-cadherin–targeted Radioimmunotherapy with 90Y-FF-21101 Monoclonal Antibody in Solid Tumors

Pharmacokinetics of polatuzumab vedotin in combination with R/G-CHP in patients with B-cell non-Hodgkin lymphoma

Considerations for setting occupational exposure limits for novel pharmaceutical modalities

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