Antibody Basics: Part 10 - Therapeutic targets - Infectious Diseases

Welcome to Antibody Basics by Biointron, Part 10! In the last two episodes, we’ve discussed common targets for antibody drugs: cancer and autoimmune diseases. In this episode, we’ll talk about infectious diseases.

Infectious diseases are caused by pathogenic microorganisms

• Bacteria: Single-celled organisms that can cause diseases such as tuberculosis, strep throat, and urinary tract infections. Antibiotics are less expensive and easier to produce than antibodies, so they have been prioritized to treat bacterial infectious diseases.

• Viruses: Infectious agents that replicate only inside the living cells of an organism and can cause diseases such as common cold, influenza, HIV/AIDS, and COVID-19. Viral infectious diseases require knowledge of the mechanism of infection for a virus and a host cell. Viruses invade host cells to parasitize and replicate, making it difficult for the host immune system to recognize it as a foreign enemy.

Antibody drugs are used for both:

• Prophylaxis: Preventing infections in high-risk individuals, such as immunocompromised patients or those exposed to infectious agents. E.g. Pemgarda (pemivibart), a long-acting mAb, for the preexposure prophylaxis of COVID-19.

• Treatment: Managing and treating active infections, after exposure to a pathogen. E.g. Ebanga (Ansuvimab) is a human mAb that targets the EBOV glycoprotein to treat Zaire ebolavirus

Exploiting pathogen weaknesses: viral envelope proteins

Prime Targets for Entry Inhibition: Envelope proteins are embedded proteins in the viral envelope, which is a membranous outer layer surrounding the viral core. They are crucial for:

• Attachment: Binding to host cell receptors. •Fusion: Merging the viral envelope with the host cell membrane. •Entry: Delivering the viral genome into the host cell.

• Neutralizing epitopes: Specific regions on envelope proteins essential for function, targeted by antibodies.

• E.g. Palivizumab, an mAb that binds to the fusion protein on the envelope of RSV. This fusion protein is a critical component for the virus to enter host cells, particularly in the respiratory tract.

Optimizing therapeutic potential through antibody engineering

• Humanization of Murine Antibodies: Immunogenicity: Murine mAbs are foreign proteins to the human immune system. This can trigger the body to develop an immune response (HAMA response) which can cause allergic reactions. Humanization resulted in reduced immunogenicity, improved patient tolerance, and improved pharmacokinetics.

• Antibody-Drug Conjugates (ADCs): ADCs are a novel class of drugs that combine the targeting ability of antibodies with the potent cell-killing power of cytotoxic drugs. This approach minimizes toxicity, a drawback of traditional chemotherapy that can harm healthy cells alongside cancerous ones. This targeted therapy holds immense promise, particularly including for infectious diseases due to the widespread emergence of antibiotic resistance.

Challenges and Future Directions

• Emerging Pathogen Threats and Antibody Resistance: Developing broadly neutralizing antibodies (bnAbs) that work against diverse strains is challenging. Viruses can exhibit high genetic variability, with surface proteins (targets for antibodies) differing between strains. Since antibodies are highly specific, a bnAb designed for one strain might not bind effectively to another, limiting its usefulness.

• Optimizing Antibody Delivery and Half-Life: Current antibody delivery methods, such as intravenous (IV) injection, can be difficult. More delivery options could include self-administered subcutaneous injections, inhalation therapies, and mucosal deliveries. Extending the half-life of antibodies in circulation through Fc region engineering or PEGylation, can increase antibody stability and reduce the frequency of dosing, thereby improving patient adherence.

• Antibody-antibiotic conjugates (AACs): Based on the knowledge acquired in the development of ADCs, this innovative AAC format makes use of the selectivity, favorable pharmacokinetic, and safety of antibodies, allowing the administration of more potent antibiotics with less off-target effects. AACs’ development is challenging due to the complexity of the three components: the antibody, the antibiotic, and the linker. However, some successful examples are currently under clinical studies, e.g. DSTA4637A to eliminate intracellular Staphylococcus aureus, which has completed Phase 1 trials.

16 antibody drugs in infectious diseases are approved

• Synagis (palivizumab): Approved in 1998, it targets an epitope in the A antigenic site of the F protein of RSV to prevent severe disease by respiratory syncytial virus infection.

• Evusheld (tixagevimab with cilgavimab): Approved in the EU in 2022, it targets the surface spike protein of SARS-CoV-2 to prevent COVID-19. 

• Zinplava (bezlotoxumab): Approved in 2016, it targets Clostridium difficile toxin B to prevent C. difficile infection recurrence

• Beyfortus (nirsevimab): Approved in 2023, it targets the fusion protein on the surface of the respiratory syncytial virus to prevent RSV.