Frank Barletta

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Mathematical modeling can integrate PK, PD and toxicodynamic (TD) data, and can generate and answer key hypotheses. Modeling and simulation techniques can be applied to optimize study design and augment/refine preclinical and clinical experimentation. Additionally, modeling can be instrumental in providing a quantitative framework for preclinical to(More)
The stability of the connection between the antibody and the toxin can have a profound impact on ADC safety and efficacy. There has been increasing evidence in recent years that maleimide-based ADCs are prone to payload loss via a retro-Michael type reaction. Herein, we report a mild method for the hydrolysis of the succinimide-thioether ring which results(More)
Author for correspondence: Department of Pharmacokinetics, Dynamics & Metabolism, Pfizer Global Research & Development, Eastern Point Rd, Groton, CT 06340, USA Tel.: +1 860 715 0641 Fax: +1 860 715 9501 E-mail: Xiaogang Han Department of Pharmacokinetics, Dynamics & Metabolism, Pfizer Global Research & Development, CT, USA Lindsay(More)
PURPOSE Triple-negative breast cancer (TNBC) and ovarian cancer each comprise heterogeneous tumors, for which current therapies have little clinical benefit. Novel therapies that target and eradicate tumor-initiating cells (TIC) are needed to significantly improve survival. EXPERIMENTAL DESIGN A panel of well-annotated patient-derived xenografts (PDX) was(More)
Disease relapse after treatment is common in triple-negative breast cancer (TNBC), ovarian cancer (OVCA), and non-small cell lung cancer (NSCLC). Therapies that target tumor-initiating cells (TICs) should improve patient survival by eliminating the cells that can drive tumor recurrence and metastasis. We demonstrate that protein tyrosine kinase 7 (PTK7), a(More)
The reactive thiol of cysteine is often used for coupling maleimide-containing linker-payloads to antibodies resulting in the generation of antibody drug conjugates (ADCs). Currently, a numbers of ADCs in drug development are made by coupling a linker-payload to native or engineered cysteine residues on the antibody. An ADC conjugated via hinge-cysteines to(More)
AIM Complex nature of bioconjugates require multiple bioanalytical approaches to support PK and absorption, distribution, metabolism and excretion characterization. For antibody-drug conjugate (ADC) bioanalysis both LC-MS and ligand-binding assays (LBAs) are employed. RESULTS A method consisting of immunocapture extraction of ADC from biomatrices followed(More)
There is a considerable ongoing work to identify new cytotoxic payloads that are appropriate for antibody-based delivery, acting via mechanisms beyond DNA damage and microtubule disruption, highlighting their importance to the field of cancer therapeutics. New modes of action will allow a more diverse set of tumor types to be targeted and will allow for(More)
As antibody-drug conjugate (ADC) design is evolving with novel payload, linker, and conjugation chemistry, the need for sensitive and precise quantitative measurement of conjugated payload to support pharmacokinetics (PK) is in high demand. Compared to ADCs containing noncleavable linkers, a strategy specific to linkers which are liable to pH, chemical(More)
A bispecific immunomodulatory biotherapeutic molecule (P-cadherin LP-DART) based on the Dual Affinity Re-Targeting (DART) scaffold has been developed as a potential antitumor treatment showing efficacy in preclinical testing. A minimal anticipated biological effect level (MABEL) approach was applied to project the first-in-human (FIH) dose, because of its(More)