Mohammad Tabrizi

Elimination mechanisms of therapeutic monoclonal antibodies.

Targeted therapies using monoclonal antibodies have achieved important therapeutic applications in the treatment of various human diseases. Understanding the factors that impact the pharmacokinetics of monoclonal antibodies is of high importance for effective therapy. Many factors related to the target antigen, antibody and patients can affect antibody elimination. Evaluation of these factors will facilitate the understanding of the processes involved in antibody elimination.

Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease

The monoclonal antibody market continues to witness an impressive rate of growth and has become the leading source of expansion in the biologic segment within the pharmaceutical industry. Currently marketed monoclonal antibodies target a diverse array of antigens. These antigens are distributed in a variety of tissues such as tumors, lungs, synovial fluid, psoriatic plaques, and lymph nodes. As the concentration of drug at the proximity of the biological receptor determines the magnitude of the observed pharmacological responses, a significant consideration in effective therapeutic application of monoclonal antibodies is a thorough understanding of the processes that regulate antibody biodistribution. Monoclonal antibody distribution is affected by factors such as molecular weight, blood flow, tissue and tumor heterogeneity, structure and porosity, target antigen density, turnover rate, and the target antigen expression profile.

A Human Monoclonal Anti-ANG2 Antibody Leads to Broad Antitumor Activity in Combination with VEGF Inhibitors and Chemotherapy Agents in Preclinical Models

Localized angiopoietin-2 (Ang2) expression has been shown to function as a key regulator of blood vessel remodeling and tumor angiogenesis, making it an attractive candidate for antiangiogenic therapy. A fully human monoclonal antibody (3.19.3) was developed, which may have significant pharmaceutical advantages over synthetic peptide-based approaches in terms of reduced immunogenicity and increased half-life to block Ang2 function. The 3.19.3 antibody potently binds Ang2 with an equilibrium dissociation constant of 86 pmol/L, leading to inhibition of Tie2 receptor phosphorylation in cell-based assays. In preclinical models, 3.19.3 treatment blocked blood vessel formation in Matrigel plug assays and in human tumor xenografts. In vivo studies with 3.19.3 consistently showed broad antitumor activity as a single agent across a panel of diverse subcutaneous and orthotopic xenograft models. Combination studies of 3.19.3 with cytotoxic drugs or anti–vascular endothelial growth factor agents showed significant improvements in antitumor activity over single-agent treatments alone with no apparent evidence of increased toxicity. Initial pharmacokinetic profiling studies in mice and nonhuman primates suggested that 3.19.3 has a predicted human half-life of 10 to 14 days. These studies provide preclinical data for 3.19.3 as a potential new antiangiogenic therapy as a single agent or in combination with chemotherapy or vascular endothelial growth factor inhibitors for the treatment of cancer. Mol Cancer Ther; 9(1); 145–56

Dual IGF-I/II-neutralizing antibody MEDI-573 potently inhibits IGF signaling and tumor growth.

Insulin-like growth factors (IGF), IGF-I and IGF-II, are small polypeptides involved in regulating cell proliferation, survival, differentiation, and transformation. IGF activities are mediated through binding and activation of IGF-1R or insulin receptor isoform A (IR-A). The role of the IGF-1R pathway in promoting tumor growth and survival is well documented. Overexpression of IGF-II and IR-A is reported in multiple types of cancer and is proposed as a potential mechanism for cancer cells to develop resistance to IGF-1R-targeting therapy. MEDI-573 is a fully human antibody that neutralizes both IGF-I and IGF-II and inhibits IGF signaling through both the IGF-1R and IR-A pathways. Here, we show that MEDI-573 blocks the binding of IGF-I and IGF-II to IGF-1R or IR-A, leading to the inhibition of IGF-induced signaling pathways and cell proliferation. MEDI-573 significantly inhibited the in vivo growth of IGF-I- or IGF-II-driven tumors. Pharmacodynamic analysis demonstrated inhibition of IGF-1R phosphorylation in tumors in mice dosed with MEDI-573, indicating that the antitumor activity is mediated via inhibition of IGF-1R signaling pathways. Finally, MEDI-573 significantly decreased (18)F-fluorodeoxyglucose ((18)F-FDG) uptake in IGF-driven tumor models, highlighting the potential utility of (18)F-FDG-PET as a noninvasive pharmacodynamic readout for evaluating the use of MEDI-573 in the clinic. Taken together, these results demonstrate that the inhibition of IGF-I and IGF-II ligands by MEDI-573 results in potent antitumor activity and offers an effective approach to selectively target both the IGF-1R and IR-A signaling pathways.

Translational strategies for development of monoclonal antibodies from discovery to the clinic

Successful strategies for the development of monoclonal antibodies require integration of knowledge with respect to target antigen properties, antibody design criteria such as affinity, isotype selection, Fc domain engineering, PK/PD properties and antibody cross-reactivity across species from the early stages of antibody development. Biophysical measurements are one of the critical components necessary for the design of effective translational strategies for lead selection and evaluation of relevant animal species for preclinical safety and efficacy studies. Incorporation of effective translational strategies from the early stages of the antibody development process is a necessity; when considered it not only reduces development time and cost, but also fosters implementation of rational decision-making throughout all phases of antibody development.

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

The advancement of therapeutic monoclonal antibodies during various stages of the drug development process can be effectively streamlined when appropriate translational strategies are applied. Design of successful translational strategies for development of monoclonal antibodies should allow for understanding of the dose– and concentration–response relationships with respect to both beneficial and toxic effects from early phases of drug development. Evaluation of relevant biomarkers during early stages of drug development should facilitate the successful design of safe and effective dosing strategies. Moreover, application of quantitative pharmacology is critical for translation of exposure–response relationships early on.

Antibody Drug Conjugates: Application of Quantitative Pharmacology in Modality Design and Target Selection

Antibody drug conjugates (ADCs) are a multi-component modality comprising of an antibody targeting a cell-specific antigen, a potent drug/payload, and a linker that can be processed within cellular compartments to release payload upon internalization. Numerous ADCs are being evaluated in both research and clinical settings within the academic and pharmaceutical industry due to their ability to selectively deliver potent payloads. Hence, there is a clear need to incorporate quantitative approaches during early stages of drug development for effective modality design and target selection. In this review, we describe a quantitative approach and framework for evaluation of the interplay between drug- and systems-dependent properties (i.e., target expression, density, localization, turnover, and affinity) in order to deliver a sufficient amount of a potent payload into the relevant target cells. As discussed, theoretical approaches with particular considerations given to various key properties for the target and modality suggest that delivery of the payload into particular effect cells to be more sensitive to antigen concentrations for targets with slow turnover rates as compared to those with faster internalization rates. Further assessments also suggest that increasing doses beyond the threshold of the target capacity (a function of target internalization and expression) may not impact the maximum amount of payload delivered to the intended effect cells. This article will explore the important application of quantitative sciences in selection of the target and design of ADC modalities.

Population Pharmacokinetic Evaluation of a Fully Human IgG2 Monoclonal Antibody in Patients with Inflammatory Diseases

ABX-IL8 is a fully human IgG₂ monoclonal antibody generated using transgenic mouse technology (Xenomouse®) that binds to human Interleukin-8 with high affinity and specificity. The objective of this study was to evaluate the pharmacokinetic (PK) properties of ABX-IL8 in patients with active inflammatory diseases. Patients with psoriasis and rheumatoid arthritis received single or multiple short intravenous infusions of ABX-IL8 or placebo. Serum concentrations of ABX-IL8, baseline serum IgG and IgG₂ concentrations and Anti-Drug Antibody (ADA) response to ABX-IL8 were determined using relevant immunoassays. Pharmacokinetic analyses of the serum ABX-IL8 concentration-time data were performed. Following single-dose administration of ABX-IL8, dose proportional increases in drug exposure were observed. Consistent with the disposition properties of the endogenous IgG antibodies, ABX-IL8 appeared to be primarily distributed into the plasma compartment and the extra-vascular fluid and the steady-sate volume of distribution (61 ± 14 to 71 ± 14 mL/kg) was comparable to that for the endogenous antibodies. Following the multiple-dose administration, PK properties of the antibody were linear with dose and time. Steady-state clearance (2.6 ± 1.1 to 2.7 ± 1.4 mL/day/kg) was similar to that observed following the single dose administration and no ADA response was detected throughout the study. PK variability and serum exposure to ABX-IL8 following administration of the fixed doses were comparable to those observed following administration of the weight-adjusted doses; the impact of body weight on clearance was minimal and this correlation did not translate into requirements for body weight-adjusted dosing. Additionally, age and disease type (psoriasis or RA) had no impact on ABX-IL8 pharmacokinetics.

Surrogate approaches in development of monoclonal antibodies

When cross-reactivity of a lead antibody across species is limited, antibody development programs require the generation of surrogate molecules or surrogate animal models necessary for the conduct of preclinical pharmacology and safety studies. When surrogate approaches are employed, the complexities and challenges for translation of preclinical safety and efficacy results to the clinic are undoubtedly enhanced. Because there are no currently established criteria or regulatory guidance regarding the application of surrogate approaches, a science-based strategy for translation of preclinical information to the clinic is vital for effective development of the lead antibody.

Abstract 4521: Evaluation of the relationship between serum exposure, receptor (GITR) availability and tumor suppression following administration of the anti-GITR antibody DX400 in mouse syngeneic tumor models

GITR is a type I transmembrane protein of the tumor necrosis factor receptor superfamily which is expressed primarily on T lymphocytes and natural killer cells. Ligation of GITR on activated T cells provides a costimulatory signal that positively modulates antigen-specific T cell responses, leading to enhanced cellular and humoral immunity. The anti-GITR antibody DX400 is a murinized agonistic monoclonal antibody that targets mouse GITR, and has shown tumor growth inhibition in mouse syngeneic tumor models. In this study we examined the pharmacokinetic/pharmacodynamics (PK/PD) properties of DX400. Studies were conducted to examine the potential relationships between anti-GITR antibody serum exposure (PK) and receptor availability (PD) on the relevant T-cell subsets. The concentrations of DX400 in serum were determined using an electrochemiluminescence (ECL) assay, and the availability of receptor (GITR) was determined using flow cytometry. Non-linear PK properties for DX400 were observed over the dose range examined. In line with changes in serum concentration-time profiles for the antibody, a dose dependent effect in receptor availability was also observed. The relationships between receptor availability, serum concentrations of DX400 and tumor suppression were described by a mechanistic PK/PD model. This analysis provided an estimated potency (EC50) value of 4.2 ng/mL for blood receptor engagement on T-cell subsets. Citation Format: Ayse Meric Ovacik, Natalie Shinsky-Bjorde, Douglas Hodges, Svetlana Antonenko, Roanna Ueda, Smita Mauze, Danling Gu, Derek Wiswell, Shuli Zhang, Amy Beebe, Mohammad Tabrizi. Evaluation of the relationship between serum exposure, receptor (GITR) availability and tumor suppression following administration of the anti-GITR antibody DX400 in mouse syngeneic tumor models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4521. doi:10.1158/1538-7445.AM2015-4521