Novel Inhaled Antibody-Drug Conjugates for Treating Tuberculosis
Abstract
This proposal was developed for the Peer Reviewed Medical Research Program and specifically the topic of tuberculosis (TB). TB is an infectious disease that generally affects the lungs in humans and is caused by the bacterium Mycobacterium tuberculosis (Mtb). The classic symptoms of TB are chronic cough, blood in sputum, fever, and night sweats. The disease is spread by those with active TB through the air, by coughing or even speaking. One-third of the global population is understood to be infected with TB. The disease has shadowed mankind for millennia as the earliest known case in human remains was dated to over 4,000 years ago, and still today the disease continues to kill 1.5 million people every year and to infect approximately 9 million. The incidence of TB in the United States military has mirrored incidence in the underlying population, suggesting that development of an effective treatment for those in the military will also be useful for civilians. Despite the availability of effective treatments for the disease, the impacts of drug resistance and morbidity of patients co-infected with HIV/AIDS have stimulated research on new quicker acting (less than the current 6-month minimum) treatments efficacious against drug-resistant infections that are less toxic when used with anti-retrovirals used for HIV/AIDS. A major hurdle for new TB therapies is to sterilize the infection in the macrophage – a cell of the immune system where Mtb apparently can hide from drugs. This represents a central and critical problem in treating TB: targeting the macrophage. Recent success with a relatively new class of therapeutics called antibody-drug conjugates (ADC) for treatment of cancers uses an antibody linked to an oncology drug so that the treatment can be targeted to tumors and not healthy cells. An antibody (Ab), also known as an immunoglobulin, is a large, Y-shaped protein produced and used by the immune system to identify and neutralize pathogens such as bacteria. The Ab attached to the cancer drug binds to the target cancer cell, is internalized, and then kills the cancer cell. Considered in this proposal is the linkage of a drug for TB with an Ab to a macrophage surface receptor. The hypothesis is that Ab’s homed to the macrophage will increase the amount of drug delivered to where Mtb is hiding. While based loosely on the strategy to deliver toxic anticancer drugs, the strategy is novel by its focus on TB and the way in which drug performance is attempted to be enhanced. The drug will not be toxic to cells, rather it will be released in macrophages that harbor the bacteria and then it will deliver the drug to kill only the bacterial cells. For the choice of drug, a widely used and safe antibacterial called meropenem was initially selected, which has to date shown some promise experimentally but also limitations against TB. This drug is not currently approved for use against TB. Published work suggests this is in large part due to the inability of meropenem to accumulate within the macrophage. A strategy is proposed to chemically link an antibody to meropenem and clavulanic acid using a linker that was previously used in one of the Food and Drug Administration (FDA)-approved ADCs. In addition, three other carbapenems will be assessed. Thus, surveying different carbapenem and clavulanic acid ADCs for their stability in plasma and ability to accumulate within the macrophage and also kill the Mtb hiding there without adversely affecting the macrophage itself will be important. Carbapenems and clavulanic acid used in ADCs with favorable results in these tests will be studied further for their ability to be dosed in guinea pigs, as models of the human host, and maintain concentrations in the blood over a period of time that would suggest suitable concentrations would reach the macrophages in infected guinea pig. The best compound will be tested in a guinea pig model of TB infection to determine whether the a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810802
Entities
People
- Sean Ekins
Organizations
- United States Army