Immune Aspects of Biopharmaceuticals and Nanomedicines

Raj Bawa, Janos Szebeni, Thomas J Webster, Gerald F. Audette, Raj Bawa, Janos Szebeni, Thomas J Webster, Gerald F. Audette

• Publisher: Jenny Stanford Publishing
• Year: 2019
• ISBN:
  9781351399777
• Edition: 1
• Topic: Medizin
• Subtopic: Biotechnologie in der Medizin

The enormous advances in the immunologic aspects of biotherapeutics and nanomedicines in the past two decades has necessitated an authoritative and comprehensive reference source that can be relied upon by immunologists, biomedical researchers, clinicians, pharmaceutical companies, regulators, venture capitalists, and policy makers alike. This text provides a thorough understanding of immunology, therapeutic potential, clinical applications, adverse reactions, and approaches to overcoming immunotoxicity of biotherapeutics and nanomedicines. It also tackles critical, yet often overlooked topics such as immune aspects of nano-bio interactions, current FDA regulatory guidances, complement activation-related pseudoallergy (CARPA), advances in nanovaccines, and immunogenicity testing of protein therapeutics.

Chapter 1

Current Immune Aspects of Biologics and Nanodrugs: An Overview

Raj Bawa, MS, PhD

Patent Law Department, Bawa Biotech LLC, Ashburn, Virginia, USA

The Pharmaceutical Research Institute,
Albany College of Pharmacy and Health Sciences, Albany, New York, USA

Department of Biological Sciences,
Rensselaer Polytechnic Institute, Troy, New York, USA

Copyright 2018 Raj Bawa. All rights reserved. As a service to authors and researchers, the copyright holder permits unrestricted use, distribution, online posting and reproduction of this article or unaltered excerpts therefrom, in any medium, provided the author and original source are clearly identified and properly credited. The figures in this chapter that are copyrighted to the author may similarly be used, distributed, or reproduced in any medium, provided the author and the original source are clearly identified and properly credited. A copy of the publication or posting must be provided via email to the copyright holder for archival.

Keywords: biotherapeutics, biologics, biologicals, biological products, biopharmaceuticals, biomolecular drugs, protein products, nanomedicine, nanodrugs, nanoparticulate drug formulations, nanopharmaceuticals, nanotechnology, nanomaterial, nanoscale, patents, commercialization, research and development (R&D), US Food and Drug Administration (FDA), European Medicines Agency (EMA), drug delivery systems (DDS), site-specific delivery, nanoparticles (NPs), protein aggregation, small-molecule drug, New Chemical Entities (NCEs), New Biological Entities (NBEs), New Drug Application (NDA), Biologic License Application (BLA), Bayh-Dole Act, Hatch-Waxman Act, Biologics Price Competition and Innovation Act (BPCI Act), immunotoxic effects, complement activation, immunogenicity, antidrug antibodies (ADAs), antibody–drug conjugates (ADCs), adverse drug reaction (ADR), conjugated proteins, functionalized antibodies, Federal Food, Drug, and Cosmetic Act (FD&C Act), target mediated drug disposition (TMDD), pharmacodynamic (PD), Public Health Service (PHS) Act, pharmacokinetics (PK), Humira^®, protein aggregates, active pharmaceutical ingredient (API), hypersensitivity reactions (HSR), anaphylactoid reactions, complement activation-related pseudoallergy (CARPA), Doxil^®, Ambisome^®, DaunoXome^®, Abelcet^®, Visudyne^®, Cremophor EL, PEGylated proteins, monoclonal antibodies (mABs), Humulin^®, PEGylated liposomes, accelerated blood clearance (ABC), reticuloendothelial system (RES), immune complexes (ICs), biosimilar, generic drugs, bioequivalent, interchangeable product, nanosimilars, nonbiologic complex drug (NBCD), NBCD similar, glatiramer acetate, Copaxone^®, immunomodulator clinical trials immunopharmacology immunomodulatory effects iTope™, TCED™, Epibase^®, EpiMatrix™, EpiScreen™, immunogenic epitopes, artificial intelligence (AI), single-cell genomics, user fees, druggable genome, cryo-electron microscopy (cryo-EM), epitope mapping analysis, bench-to-bedside, translation, drug-like molecule, CRISPR-Cas9

1.1 Introduction

A wave of “newer” therapeutics is sweeping the drug world. Specifically, there is a rapid introduction of two somewhat distinct yet overlapping classes of drugs into the pharmaceutical landscape: (1) biologics¹ and (2) nanodrugs.² Biologics have already entered an era of rapid growth due to their wider applications, and in the near future they will replace many existing organic based small-molecule drugs. According to one drug analysis firm, biologics have grown from 11% of the total global drug market in 2002 to around 20% in 2017.³ On the other hand, nanodrugs have sputtered along a somewhat different trajectory with greater challenges to their translation [1, 2, 3]. I estimate that since the approval of the first recombinant biologic (recombinant human insulin, in 1982), there are over 225+ marketed biologics and at least 75 nanodrugs for various clinical applications approved by various regulatory agencies.⁴ According to the Pharmaceutical Research and Manufacturers of America (PhRMA) website, as of 2013, there are over 900 biologic medicines and vaccines in development. I estimate that hundreds of companies globally are engaged in nanomedicine research and development (R&D), the clear majority of these have continued to be startups or small- to medium-sized enterprises rather than big pharma. Despite immature regulatory mechanisms, follow-on versions of these two drug classes, namely biosimilars and nanosimilars, respectively, have also started to trickle into the marketplace.

According to the US Food and Drug Administration (FDA), the products it regulates represent around 20% of all products sold in the United States, representing more than $2.4 trillion. The FDA regulates products according to specific categories: food, dietary supplements, cosmetics, drugs, biologics, medical devices, veterinary products, and tobacco. The Center for Biologics Evaluation and Research (CBER) regulates what are often referred to as traditional biologics, such as vaccines, blood and blood products, allergenic extracts, and certain devices and test kits. CBER also regulates gene therapy products, cellular therapy products, human tissue used in transplantation, and the tissue used in xenotransplantation—the transplantation of nonhuman cells, tissues, or organs into a human. On the other hand, the Center for Drug Evaluation and Research (CDER) regulates branded and generic drugs, over-the-counter (OTC) drugs, and most therapeutic biologics (Fig. 1.1a). Food, dietary supplements, and cosmetics fall under the jurisdiction of the Center for Food Safety and Nutrition (CFSAN). Since dietary supplements are intended to supplement the diet, they are classified under the “umbrella” of foods and do not require premarket authorization from the FDA. Cosmetics containing sunscreen components are regulated as drugs. In these cases, the products must be labeled as OTC drugs and meet OTC drug requirements. Tobacco products are subject to a unique regulatory framework as they only pose risks without providing any health benefits. They are regulated by the Center for Tobacco Products (CTP). Medical devices are regulated by the Center for Devices and Radiological Health (CDRH), and veterinary products by the Center for Veterinary Medicine (CVM). Drugs that have high potential for abuse with no accepted medical use are illegal and cannot be imported, manufactured, distributed, possessed, or used. The Drug Enforcement Administration (DEA) is the US agency tasked with overseeing these dangerous products and enforcing the controlled substances laws. The Office of Combination Products (OCP) has authority over the regulatory life cycle of combination products. Combination products are therapeutic and diagnostic products that combine drugs, devices, and/or biological products. As technological advances continue to merge product types and blur the historical lines of separation between various FDA centers, I expect that more products in the near future will fall into the category of combination products. Naturally, this will present unique regulatory, policy, and review management challenges.

The main law that governs various products in the United States is the Federal Food, Drug, and Cosmetic Act (FD&C Act). It was established in 1938 and has been amended numerous times since. The laws are passed as Acts of Congress and organized/codified into United States Code (USC). Of the 53 titles in the USC, title 21 corresponds to the FD&C Act. To operationalize the law for enforcement, federal agencies, including the FDA, are authorized to create regulations. The Code of Federal Regulations (CFR) details how the law will be enforced. The CFR is divided into 50 titles according to subject matter. Therefore, there are three types of references for regulatory compliance: FD&C Act, 21USC, and 21CFR. The FD&C Act provides definitions for the different product categories along with allowable claims. For example, drugs, biologics, and medical devices can make therapeutic claims like “treatment of a particular disease” or “reduction of symptoms associated with a particular disease.” Therapeutic claims also include implied statements like “relieves nausea” or “relieves congestion.” It is illegal for nonmedical products like pharma-cosmetics, dietary supplements, and cosmetics to make therapeutic claims. Even if a product lacks any therapeutic ingredient, its intended use may cause it to be categorized as a drug.

This chapter focuses on those biologics, biotechnology products, nanomedicines, nanodrug products, and nanomaterials that are used for medicinal purposes in humans. Many biologics (e.g., monoclonal antibodies or drug-protein conjugates) are of nanoscale and hence can also be considered to be nanodrugs. Conversely, many nanodrugs are biologics according to standard definitions (Sections 1.2 and 1.3). For example, Copaxone^® (Section 1.7) is a biologic (Section 1.2) but also falls within the definition of a nanodrug (Section 1.3). Many terms used here are definitions that come from specific regulations or compendia. The terms “product,” “drug formulation,” “therapeutic product,” or “medicinal product” will be used in the manner the FDA defines a “drug,” encompassing pharmaceutical drugs, biologics, and nanomedicines in the context of describing the final “drug product.” Some of the terms will be used synonymously. For example, biotherapeutics, protein drugs, biologicals, biological products, and biologics are equivalent terms.¹ Similarly, nanomedicines, nanodrugs, nanopharmaceuticals, nanoparticulate drug formulations, and nanotherapeutics are the same.² Branded drugs are referred to as “pioneer,” “originator,” “branded,” or “reference” drugs. Small-molecule drugs approved by the FDA are known as New Chemical Entities (NCEs) while approved biologics are referred to as New Biological Entities (NBEs) (Fig. 1.1a, Table 1.1, and Box 1.1). As a result, a new drug application for an NCE is known as a New Drug Application (NDA) while a new drug application for an NBE is known as a Biologic License Application (BLA). Note that prior to the 1980s, there were very few marketed biologics, so the very term “pharmaceutical” or “drug” implied a small-molecule drug. Although biologics are subject to federal regulation under the Public He...