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Antibody-based drugs offer new mechanisms of action and greater specificity.
The rise of antibiotic-resistant bacteria is recognized as a significant threat to the future practice of medicine. Continually rising resistance rates have resulted in infections with bacteria resistant to all existing antibiotic treatment options. There is concern that if the current treatment system remains unchanged, the resistance epidemic could push the world into a post-antibiotic era.
Alternatives are therefore needed to replace current small-molecule antibiotics. Given that the development of resistance is a natural form of evolution for bacteria, the challenge is to find new drugs that kill bacteria in a way that dramatically slows down their ability to counteract them. Biologic drug substances-monoclonal antibodies (mAbs) in particular-may be a key component of the solution.
Regardless of the antibiotic, resistance will develop, according to MedImmune’s director of microbial sciences Bret Sellman. “Most available antibiotics are related to natural products for which resistance already exists in nature,” he explains. Bacteria also divide rapidly, which increases the likelihood for antibiotic-resistant mutants to evolve.
In addition, over the past four decades there have been few truly novel antibiotics, according to James Levin, director of preclinical development at Cidara Therapeutics. “We have been targeting the same limited subset of essential proteins, and therefore, bacteria have ample opportunity to evolve and become resistant to entire antibiotic classes over time,” he observes.
Sellman argues that development of antibiotic resistance has less to do with the structure or chemistry of antibiotics than it does their method of attacking a pathogen and their widespread use in modern medicine and farming. “By killing bacteria directly, antibiotics select for the outgrowth of resistant mutants. In addition, the misuse of antibiotics to treat viral diseases (e.g., the common cold) unnecessarily exposes patients and their bacteria to antibiotics and fails to treat the actual disease being experienced. This ease of access only increases exposure and subsequently the risk of resistance,” he asserts.
Resistance can arise from chemical modification of the antibiotic by bacterial enzymes or mutations to the antibiotic target, adds Levin. He also notes that bacteria are able to swap genes that impart antibiotic resistance with other bacteria, allowing resistance to spread rapidly.
Adding to these escape mechanism issues, Levin points out that gram-negative bacteria are intrinsically resistant to many antibiotics because they possess an outer membrane that is impermeable to most drugs-and they can mutate to reduce permeability further when under selective pressure.
There is an additional problem associated with the use of broad-spectrum antibiotics: they kill not only harmful pathogens, but “good” bacteria that make up the microbiome within humans. Doing so results in the development of resistance in the target pathogen as well as the members of healthy microbiome, which can then transfer resistance to pathogens they encounter, further spreading the problem, according to Sellman.
Damage to the healthy microbiome can have significant consequences as well. “Killing of the healthy microbiome has been linked not only to the development of Clostridium difficile diarrhea but also diabetes, obesity, immune defects, and antibiotic resistance spread through gene transfer,” he says.
While antibiotics will always play an important role in saving and preserving life, the growing antibiotic resistance epidemic and increasing understanding of the adverse effects of broad-spectrum antibiotics on the healthy microbiome necessitate the development of alternatives such as pathogen-specific strategies to prevent or treat bacterial infections, according to Sellman. “We firmly believe that moving away from traditional small molecules is the path forward in anti-infectives research,” Levin agrees.
Most efforts are focused on new drugs based on mAbs because of their specificity. “Such targeted antibacterials should have reduced toxicity, cause less harm to patients’ beneficial microbiomes, and not promote resistance in bacteria not targeted,” Sellman comments.
Antibacterial mAbs also directly neutralize bacterial virulence mechanisms and engage the patient’s immune system, according to Sellman. “By boosting the immune system to kill the pathogen rather than killing the bacteria directly, the emergence of resistance might be reduced,” he explains.
Cidara Therapeutics is developing antimicrobial antibody-drug conjugates (ADCs). “These bispecific molecules capitalize on the potency of antibiotics coupled with the beneficial aspects of an effective and robust immune response and can be designed with a prolonged half-life,” says Levin. He believes that any antimicrobial, including small molecules, that binds to a surface or cell-wall component of the bacterium is a viable candidate for conjugation to an antibody fragment crystallizable (Fc) region.
In addition to antibody-based drug candidates, Sellman notes that researchers across industry and academia are also exploring phage lysins and viral phage approaches as alternatives to small-molecule antimicrobials.
Development of mAb antimicrobial drugs does not come without challenges, but those difficulties are not solely in the scientific arena. “In order to realize the promise of biologics in infectious disease, we need to evolve the way we plan to manufacture and diagnose for these medicines,” Sellman states. Because antibacterial mAbs would likely be most effective in the earlier stages of infections, a move to integrate mAbs into the mainstream infectious disease protocol would require a commitment to more rapid diagnostic methods.
In addition, he notes that because pathogen-specific mAb treatments must account for bacterial strain diversity and the expression of multiple virulence determinants by the infecting pathogen, mAb combinations may be required for optimal efficacy.
The higher cost of biologic antibiotic drug substances compared to their small-molecule counterparts could also be an issue, according to Levin. His hope is, though, that the significantly longer half-life that should be achievable for biologic antibiotics, including ADCs, will enable less frequent dosing and thus offset the higher cost.
Cidara Therapeutics set out to develop ADC antibiotics that exert a direct killing effect on the pathogen; engage the immune system, bringing a second mechanism of killing into play; potentiate standard-of-care antibiotics by attacking the bacterial cell wall and allowing them to penetrate the cell more effectively; and have superior (antibody-like) pharmacokinetic and distribution properties.
The company conjugates surface-acting antimicrobials (targeting moieties [TMs]) to Fc regions of human antibodies using non-cleavable linkers. The bispecific Cloudbreak ADCs exert direct killing activity on bacteria while targeting the cell for destruction by the immune system, according to Levin. “We believe that by developing drugs with a dual killing mechanism we will reduce the opportunity for the target pathogen to develop resistance. In addition, since our TMs do not have to reach the inside of the cell to kill the bacterium, we avoid the daunting problem of having to breach the bacterial membrane in gram-negative bacteria,” he says. In addition, because antibodies can remain at effective concentrations in plasma for a month or longer, Cidara believes its ADCs can ultimately be engineered to achieve a similar half-life.
The company recently demonstrated proof of concept with an ADC comprising a peptidic antimicrobial conjugated to a human Fc. “Although not our final drug candidate, this ADC was efficacious in murine Acinetobacter and Pseudomonas pneumonia models. It also demonstrated a much longer half-life than the polypeptide alone,” Levin notes. In-house characterization by Cidara’s immunology team further demonstrated the ability of this conjugate to successfully engage the immune system to enhance bacterial killing. Some of this work was performed in collaboration with Professor Ashraf Ibrahim at UCLA and has yielded important insights into the mechanism of action of ADCs.
The Cloudbreak ADCs are in preclinical development, but Levin expects a clinical candidate to be nominated in 2019. Current efforts are focused on evaluation of lead candidates in preclinical toxicology studies and exploration of Fc modifications to further extend in-vivo half-life. The company received a National Institutes of Health grant in 2018 in conjunction with Professor David Perlin at Rutgers that should accelerate the pace of its ADC program, according to Levin. Cidara is also applying its Cloudbreak technology to the development of antivirals.
Within MedImmune, the global biologics research and development arm of AstraZeneca, two Phase II mAb assets are in clinical testing. MEDI4893 (suvratoxumab) is under investigation for the prevention of Staphylococcus aureus pneumonia in intensive care unit patients, while MEDI3902 is being developed for the prevention of Pseudomonas aeruginosa pneumonia in intensive care unit patients.
“As we continue to explore this field, we are constantly learning about the critical role of the commensal microbiome in maintaining overall health, and even the role it can play in possibly treating certain diseases. With this understanding comes a commitment to exploring new therapeutic options that avoid damaging these beneficial bacteria. The targeting specificity of biologics offers tremendous promise in making this goal a reality,” Sellman concludes.
Vol. 42, No. 12
When referring to this article, please cite it as C. Challener, " Fighting Bacterial Resistance with Biologics," Pharmaceutical Technology 42 (12) 2018.