Tumor-Targeted Immunomodulators

Bispecific antibodies (BsAbs) are artificial antibodies that simultaneously bind to two different antigens or epitopes, combining the specificity and bifunctionality of two monoclonal antibodies (mAbs) in one molecule. BsAbs, not naturally occurring, are produced through various technologies like cell fusion or recombinant DNA engineering. Developed for over 50 years, BsAbs have evolved from simple hybrid molecules to complex and diverse structures. They can be classified based on structure, valency, format, and production method, including Fc-deficient BsAbs, symmetric BsAbs, and asymmetric BsAbs. Each type has its own advantages and disadvantages concerning size, stability, pharmacokinetics, immunogenicity, toxicity, and production. BsAbs show significant potential in treating various diseases, especially cancer and inflammatory disorders. One of the most promising applications is tumor-targeted immunomodulators (TTIMs), BsAbs modulating the immune system by targeting tumor antigens and immune checkpoints. TTIMs enhance the anti-tumor immune response by recruiting immune cells, activating or inhibiting immune receptors or enzymes, or delivering active agents to tumor sites. Demonstrating remarkable efficacy and safety in preclinical and clinical studies, TTIMs are a hot topic in cancer immunotherapy.

The Mechanism of Action of Tumor-Targeted Immunomodulators

Tumor-targeted Immunomodulators (TTIMs) are a type of bispecific antibodies (BsAbs) that modulate the immune system by targeting tumor antigens and immune checkpoints. Immune checkpoints are molecules regulating the activation and inhibition of immune cells, such as T cells, capable of recognizing and killing cancer cells. However, some cancer cells evade immune attacks by expressing checkpoint ligands or receptors binding to corresponding molecules on T cells, suppressing their function. TTIMs work by binding to two different antigens or epitopes with their two arms: one arm binds to a tumor antigen expressed on the surface of cancer cells, and the other arm binds to an immune checkpoint molecule expressed on the surface of T cells or other immune cells. Thus, TTIMs achieve several effects: bringing T cells and cancer cells into close proximity, increasing the chance of T cell activation and cytotoxicity; blocking the interaction between the checkpoint ligand and receptor, preventing the inhibition of T cell function and restoring their anti-tumor activity; crosslinking the checkpoint receptor or ligand, triggering a signaling cascade that can either activate or inhibit the immune cell depending on the type of checkpoint molecule; delivering an active agent, such as a cytokine or a toxin, to the tumor site, enhancing the local immune response or directly killing cancer cells.

Characteristics of Tumor-Targeted Immunomodulators

Tumor-targeted immunomodulators (TTIMs) have several distinctive features that differentiate them from other types of BsAbs or monoclonal antibodies (mAbs). First, they have a tumor-specific arm and an immune-specific arm, increasing the specificity and efficacy of therapy by targeting two or more antigens simultaneously. Second, they have a modular design, allowing the combination of different tumor antigens and immune checkpoints to create customized therapies for different types of cancer or patients. Third, they have a flexible format, varying in size, valency, structure, and production method, depending on the desired properties and functions of the TTIMs. Fourth, they have a dual mechanism of action, involving both direct and indirect effects on the tumor cells and the immune cells, such as cytotoxicity, immune activation, immune inhibition, or delivery of active agents.

However, TTIMs also face some challenges. They may have increased immunogenicity, off-target effects, or cytokine release syndrome due to their unnatural structure or function, triggering unwanted immune reactions or inflammation in the body. They may have challenging production, purification, or characterization due to their heterogeneity or diversity, affecting their quality, consistency, or stability. They may have limited clinical data or experience due to their novelty and complexity, requiring more rigorous and extensive testing and evaluation before approval for clinical use.

The Clinical and Potential Applications of Tumor-targeted Immunomodulators

Tumor-targeted immunomodulators (TTIMs) have shown great potential in treating various diseases, especially cancer and inflammatory disorders. Demonstrating remarkable efficacy and safety in preclinical and clinical studies, there are more than 40 TTIMs in different stages of clinical development, targeting various tumor antigens and immune checkpoints, according to a recent review. Moreover, TTIMs have a wide range of indications and potential applications, depending on their target antigens and immune checkpoints. In addition, TTIMs hold a promising future in the field of cancer immunotherapy and beyond.

Table 1. Some of the most advanced TTIMs in clinical development

These are some of the most advanced Tumor-Targeted Immunomodulators (TTIMs) in clinical development, as of April 2023. All of them are Bispecific Antibodies (BsAbs) capable of modulating the immune system by targeting tumor antigens and immune checkpoints. With different targets, indications, and phases, their design and performance vary. These TTIMs have demonstrated promising results in both preclinical and clinical studies, and some have either received approval or are on the verge of approval from the FDA. They epitomize the cutting-edge advancements in cancer immunotherapy and underscore the potential of TTIMs as a groundbreaking paradigm in this field.

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