Amita Datta-Mannan

Eli Lilly · Department of Drug Disposition

Carbamazepine (CBZ) is the recommended alternative to rifampicin as a CYP3A4 inducer in drug–drug interaction studies. However, the traditional CBZ dosing paradigm can lead to several adverse events (AEs). This study tested a shorter CBZ dosing regimen using the CYP3A4‐sensitive index substrate midazolam (MDZ). This was a fixed‐sequence arm of an o...

Many oncology antibody-drug conjugates (ADCs) have failed to demonstrate efficacy in clinic because of dose-limiting toxicity caused by uptake into healthy tissues. We developed an approach that harnesses ADC affinity to broaden the therapeutic index (TI) using two anti-mesenchymal-epithelial transition factor (MET) monoclonal antibodies (mAbs) wit...

Real‐world data (RWD) and real‐world evidence (RWE) are now being routinely used in epidemiology, clinical practice, and post‐approval regulatory decisions. Despite the increasing utility of the methodology and new regulatory guidelines in recent years, there remains a lack of awareness of how this approach can be applied in clinical pharmacology a...

For some patients with psoriasis, orally administered small molecule inhibitors of interleukin (IL)‐17A may represent a convenient alternative to IL‐17A‐targeting monoclonal antibodies. This first‐in‐human study assessed the safety, tolerability, pharmacokinetics (PKs), and peripherally circulating IL‐17A target engagement profile of single or mult...

Since the 21st Century Cures Act was signed into law in 2016, real-world data (RWD) and real-world evidence (RWE) have attracted great interest from the health care ecosystem globally. The potential and capability of RWD/RWE to inform regulatory decisions and clinical drug development have been extensively reviewed and discussed in the literature....

Bifunctional antibody therapeutics offer the potential for novel functionalities beyond those of the individual mono-specific entities. However, combining these entities into a single molecule can have unpredictable effects, including changes in pharmacokinetics that limit the compound's therapeutic profile. A better understanding of how molecular...

An integrated physiologically based modeling framework is presented for predicting pharmacokinetics and bioavailability of subcutaneously administered monoclonal antibodies in cynomolgus monkeys, based on in silico structure-derived metrics characterizing antibody size, overall charge, local charge, and hydrophobicity. The model accounts for antibo...

A model-based framework is presented to predict monoclonal antibody (mAb) pharmacokinetics (PK) in humans based on in vitro measures of antibody physiochemical properties. A physiologically based pharmacokinetic (PBPK) model is used to explore the predictive potential of 14 in vitro assays designed to measure various antibody physiochemical propert...

Bispecific antibodies (BsAb) that engage multiple pathways are a promising therapeutic strategy to improve and prolong the efficacy of biologics in complex diseases. In the early stages of discovery, BsAbs often exhibit a broad range of pharmacokinetic (PK) behavior. Optimization of the neonatal Fc receptor (FcRn) interactions and removal of undesi...

The neonatal Fc receptor (FcRn) represents a transport system with the potential to facilitate absorption of biologics across the gastrointestinal barrier. The features of the molecule:FcRn interaction that can improve the gastrointestinal absorption of biologics are not well understood. Thus, we studied the absorption of Fc molecules from the inte...

Monoclonal antibodies have evolved from research tools to powerful therapeutics in the past 30 years. Clinical success rates of antibodies have exceeded expectations, resulting in heavy investment in biologics discovery and development in addition to traditional small molecules across the industry. However, protein therapeutics cannot drug targets...

Many therapeutic monoclonal antibodies (mAbs) were initially developed for intravenous (IV) administration. As a means to improve mAb drug-ability and the patient experience, subcutaneous (SC) administration is an increasingly important delivery route for mAbs. Unlike IV administration, bioavailability limitations for antibodies have been reported...

Monoclonal antibodies (mAbs) are immunoglobulins designed to target a specific epitope on an antigen. Immunoglobulins of identical amino-acid sequence were originally produced by hybridomas grown in culture and, subsequently, by recombinant DNA technology using mammalian cell expression systems. The antigen-binding region of the mAb is formed by th...

LY3343544: A novel MET antibody drug conjugate that shows profound pre-clinical in vivo anti-tumor activities, irrespective of MET pathway dependence MET is over-expressed in many types of human tumors. Due to the heterogeneity of human tumors, MET antibodies or small molecule inhibitors have benefited only small subsets of patients with tumors dri...

There is a rapidly growing interest in the development of bi- or multi- functional antibody (BsAbs) based biotherapeutics due to their inherent ability to interact with many targets simultaneously, thereby potentially protracting their functionality relative to monoclonal antibodies (mAbs). Biophysical property assays have been used to improve the...

Monoclonal antibodies (mAbs) and peptides are an important class of therapeutic modalities that have brought improved health outcomes in areas with limited therapeutic optionality. Presently, there more than 90 mAb and peptide therapeutics on the United States market, with over 600 more in various clinical stages of development in a broad array of...

Among the numerous antibody-drug conjugate (ADC) clinical candidates, one of the most prevalent types utilizes the interchain cysteines in antibodies to conjugate auristatin via a maleimide-containing linker. In this class of ADCs, there are a paucity of systematic studies characterizing how IgG subclass influences the biophysical properties and in...

There is a rapidly growing reinvigoration of the investigation of small proteins, cyclic peptides and mAb derived domains as biotherapies. The drugability of these structures are challenged by fast peripheral clearance properties that can reduce their potential to be realized as medicines. Engineering strategies have been of limited value because m...

Bispecific antibodies (BsAbs) can affect multiple disease pathways, thus these types of constructs potentially provide promising approaches to improve efficacy in complex disease indications. The specific and non-specific clearance mechanisms/biology that affect monoclonal antibody (mAb) pharmacokinetics are likely involved in the disposition of Bs...

An antibody-drug conjugate (ADC) is a unique therapeutic modality composed of a highly potent drug molecule conjugated to a monoclonal antibody (mAb). As the number of ADCs in various stages of nonclinical and clinical development has been increasing, pharmaceutical companies have been exploring diverse approaches to understanding the disposition o...

FST-ΔHBS-Fc is a follistatin (FST) based Fc fusion protein currently being developed as a novel therapy for several potential indications, including muscle wasting. Previous assessments of the pharmacokinetics and therapeutic activity of FST-ΔHBS-Fc have shown a close association of the exposure-response relationship. The current work builds upon t...

The application of protein engineering technologies toward successfully improving antibody pharmacokinetics has been challenging due to the multiplicity of biochemical factors that influence monoclonal antibody (mAb) disposition in vivo. Physiological factors including interactions with the neonatal Fc receptor (FcRn) and specific antigen binding p...

Lowering the isoelectric point (pI) through engineering the variable region or framework of an IgG can improve its exposure and half-life via a reduction in clearance mediated through non-specific interactions. As such, net charge is a potentially important property to consider in developing therapeutic IgG molecules having favorable pharmaceutical...

Monoclonal antibodies (mAbs) represent an important class of therapeutic modalities. In order to optimize their pharmaceutical properties, studies have focused on improving mAb pharmacokinetic/pharmacodynamics (PK/PD) profiles by modulating their interactions with the neonatal Fc receptor (FcRn). The influence of both the chemical and physical prop...

Activin A, a member of the transforming growth factor-β superfamily, provides pleiotropic regulation of fibrosis and inflammation. We aimed at determining whether selective inhibition of activin A would provide a regenerative benefit. The introduction of activin A into normal muscle increased the expression of inflammatory and muscle atrophy genes...

Follistatin (FST) is a member of the TGFβ family and is a secreted glycoprotein that antagonizes many members of the family including Activin A, GDF11 and myostatin. The objective of this study was to explore the use of an engineered Follistatin therapeutic created by fusing FST315 lacking heparin binding activity to the N-terminus of a murine IgG1...

At least 7 distinct EGF ligands bind to and activate the EGF receptor (EGFR). This activation plays important roles in the embryo and in maintenance of adult tissues. Importantly, pharmacologic EGFR inhibition has revealed that it also plays critical roles in the pathophysiology of diverse disease states, especially cancer. The roles of specific EG...

Human follistatin is a regulatory glycoprotein with widespread biological functions including anti-inflammatory activities, wound healing properties and muscle stimulating effects. The role of follistatin in a wide range of biological activities shows promise for potential clinical application, which has prompted considerable interest in the invest...

The pH-dependent binding of IgGs to the neonatal Fc receptor (FcRn) plays a critical role in regulating IgG homeostasis in vivo. Enhancing interactions between Fc and FcRn via protein engineering has been successfully used as an approach for improving the pharmacokinetics of monoclonal antibodies (mAbs). Although the quantitative translatability of...

Engineering monoclonal antibodies (mAbs) with improved binding to the neonatal Fc receptor (FcRn) is a strategy that can extend their in vivo half-life and slow their systemic clearance. Published reports have predominantly characterized the pharmacokinetics of mAbs after intravenous administration. Recently, studies in mice suggest FcRn may also p...

The neonatal Fc receptor, FcRn mediates an endocytic salvage pathway that prevents degradation of IgG, thus contributing to the homeostasis of circulating IgG. Based on the low affinity of IgG for FcRn at neutral pH, internalization of IgG by endothelial cells is generally believed to occur via fluid-phase endocytosis. To investigate the role of Fc...

The neonatal Fc receptor (FcRn) plays a critical role in regulating IgG homeostasis in vivo. There are mixed reports on whether modification of the interaction with FcRn can be used as an engineering strategy to improve the pharmacokinetic and pharmacodynamic properties of monoclonal antibodies. We tested whether the T250Q/M428L mutations, which im...

It is well established that the neonatal Fc receptor (FcRn) plays a critical role in regulating IgG homeostasis in vivo. As such, modification of the interaction of IgG with FcRn has been the focus of protein-engineering strategies designed to generate therapeutic antibodies with improved pharmacokinetic properties. In the current work, we characte...

The specificity of chemokine-receptor interactions plays a central role in the regulation of leukocyte migration in inflammatory responses. Herein, we describe a soluble mimic of CC chemokine receptor 2 (CCR2), dubbed CROSS-N(2)E3(2), which incorporates the N-terminal region (N) and third extracellular loop (E3) elements of CCR2 displayed on the su...

To identify the elements of two chemokines [monocyte chemoattractant protein-1 (MCP-1) and eotaxin] that control their differential recognition by their respective receptors (CCR2 and CCR3), we have studied the receptor interactions of MCP-1-eotaxin chimeras. Each receptor was found to exhibit a distinct binding preference for proteins containing t...

Despite the broad biological importance of G protein-coupled receptors (GPCRs), ligand recognition by GPCRs remains poorly understood. To explore the roles of GPCR extracellular elements in ligand binding and to provide a tractable system for structural analyses of GPCR/ligand interactions, we have developed a soluble protein that mimics ligand rec...

Thesis (Ph. D.)--Indiana University, 2003.