October 31, 2022 PAO-10-022-CL-07
In the United States alone, the Centers for Disease Control and Prevention (CDC) National Center for Health Statistics estimates that, during the 12 months ending in April 2021, 100,306 people died of drug overdoses — an increase of 28.5% over the previous 12-month period.1 Three-quarters of these deaths were opioid-related, which rose from 56,064 to 75,673 — a 35% increase. Overdose deaths from synthetic opioids (primarily fentanyl) and psychostimulants, such as methamphetamine, also increased in the 12-month period ending in April 2021.
Globally, the World Health Organization (WHO) — which defines opioids as compounds extracted from the poppy seed, as well as semisynthetic and synthetic compounds with similar properties that can interact with opioid receptors in the brain — estimates that approximately 375,000 people die annually due to opioid use, with more than 30% of those deaths attributable to overdose.2
These data reflect the complexity of substance use disorders (SUD) and the drugs that lead to fatal drug overdoses, which include heroin, prescription opioids, synthetic opioids, stimulants, and designer drugs, as well as various mixtures available from drug dealers, such as fentanyl/methamphetamine and heroin/cocaine.
The U.S. Food and Drug Administration (FDA) has approved a variety of products based on three main small molecules (methadone, buprenorphine, and naltrexone) for the treatment of OUD. For the treatment of opioid overdose, naloxone remains the primary medication. These are all mu opioid receptor (MOR) agonists, partial agonists, and antagonists. Whether used alone or in various combinations, these pharmacotherapies have suboptimal efficacy, potential for side effects, and, in the case of buprenorphine and methadone, present the potential for abuse and diversion. In addition, MOR antagonism with naloxone is not as effective against fentanyl and its derivatives as it is against heroin.
Additional medications and treatment strategies are clearly needed.
One new approach involves the use of opioid conjugate vaccines as a treatment for OUD and for the prevention of opioid overdose.3-10 In this strategy, the vaccine introduces anti-opioid antibodies into the bloodstream that bind to opioids, preventing them from entering the brain and eliciting psychoactive effects.11 The result is reduced drug effects, such as antinociception, respiratory depression, and bradycardia, and less likelihood of lethality.
The vaccines comprise a drug-based hapten conjugated to a carrier protein using a linker molecule. They are formulated with an appropriate adjuvant as parenteral (injectable) products that are filled into vials for storage and distribution. The hapten is designed to be as similar to the target opioid drug as possible to ensure the production of antibodies that will be strongly attracted to the target opioid. Modifications to allow attachment to the linker must not affect the key functional groups involved in opioid biological activity. Metabolite generation must also be factored in. Similarly, the choice of the linker, carrier protein, and linker attachment chemistry must be carefully considered, as they also impact vaccine efficacy.
These vaccines are an attractive solution because they are expected to be long-lasting, safe, and selective and can potentially serve as therapeutic and prophylactic interventions to treat OUD and protect from accidental and deliberate exposure. Based on animal studies, these vaccines are not expected to interfere with other medications used to treat pain and in general critical care situations. They can also be used in combination with existing FDA-approved medications, such as methadone, buprenorphine, and naltrexone.
Several opioid conjugate vaccines are in preclinical development against various natural and synthetic prescription and illegal opioids. One research group has achieved promising results in primate and other animal models.11 Another group is developing conjugate vaccines for the treatment of fentanyl use disorder. In one example, a novel fentanyl hapten is conjugated to tetanus toxoid (TT) and adjuvanted with liposomes containing monophosphoryl lipid A adsorbed on aluminum hydroxide.12 In another, they have created a bivalent conjugate vaccine against heroin and fentanyl.13 Another set of researchers found that dmLT and LTA1 adjuvants enhanced the immunogenicity of an anti-fentanyl conjugate vaccine and promoted a robust blockade of fentanyl-induced analgesia.14
Among other promising candidates, vaccines against oxycodone (OXY-KLH); and heroin (M-KLH), the vaccine-induced antibodies have been shown to decrease opioid distribution to the brain in a dose-dependent fashion, with efficacy dependent upon the antibody response, dose, route of exposure, and target opioid.3-5,7-9,12 The data have been sufficiently promising to warrant approval by the FDA of an investigational new drug (IND) application for testing of OXY-KLH in participants with OUD.7,8,15 The placebo-controlled phase Ia/Ib clinical trial will explore two active vaccine doses of OXY-KLH, adjuvanted.
Production of opioid conjugate vaccines often involves a process similar to that used for the manufacture of antibody and protein drug conjugates and other types of bioconjugated therapeutics. A linker is first reacted with a modified hapten to form a linker–hapten intermediate. This compound is then conjugated to the carrier protein. Commonly used coupling chemistry involves either the coupling of maleimide linker groups with thiol or thiol ether moieties on the carrier protein or the use of carbodiimide (EDC) chemistry to conjugate haptens via a primary amine group to carboxylic acid moieties on the relevant carrier protein. After conjugation, the sterile drug substance is formulated with an appropriate adjuvant, often an aluminum-based material. This step can be challenging, because it can be difficult to maintain homogeneity when the drug substance is mixed with the adjuvant. In addition, the formulated product cannot be sterile filtered and thus must be subjected to an aseptic fill and finish process.
GBI, a leading CDMO with extensive antibody–drug conjugate and other bioconjugate development and manufacturing experience, is an ideal outsourcing partner for researchers and companies developing drug conjugate vaccines.16-22 For more than five years and over multiple programs, GBI has been working with clients, such as Marco Pravetoni, Ph.D., Professor of Psychiatry and Behavioral Sciences at the University of Washington School of Medicine, Seattle, WA, (formerly University of Minnesota and Hennepin Healthcare Research Institute, Minneapolis, MN) to take vaccine candidates to the clinic, including the lead compound OXY-KLH.
In this space, GBI performs conjugation reactions using haptens and carrier proteins and fill and finish to obtain an injectable product suitable for clinical testing. In the case that drug haptens are controlled substances, one of the first steps to support such collaborations is to implement the necessary policies and procedures for appropriately storing, handling, and processing controlled substances and then apply for and obtain appropriate licensing from the DEA.
With this experience and its expertise in the required DEA regulations and schedules, GBI is ideally positioned to support the process development and cGMP manufacture of many different types of such drug conjugate vaccines.
References
Dr. Sesay is the Chief Science Officer and Vice President of Bioconjugation Development at GBI. He has over 25 years of biotechnology experience in biologics process development and manufacturing, bioconjugation, and modification of biological and small molecules. Dr. Sesay has over 17 years of CDMO experience.
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