Bispecific antibodies (BsAbs) are artificial antibodies that can simultaneously bind to two different antigens, thereby enabling novel therapeutic strategies that are not possible with conventional monoclonal antibodies. BsAbs have been developed for various applications, such as redirecting immune cells to kill tumor cells, blocking two different signaling pathways, or delivering drugs or toxins to specific targets. Among these applications, targeted payload delivery is a mechanism that exploits the dual specificity of BsAbs to selectively deliver potent agents, such as cytotoxic drugs or immunotoxins, to tumor cells or other target cells, while sparing normal cells from the adverse effects. This mechanism has the potential to improve the efficacy and safety of BsAb-based therapies, and has been applied to various diseases, especially cancer.
The principle of targeted payload delivery is based on the use of bispecific antibodies (BsAbs) that can bind to two different antigens with high specificity and affinity. One arm of the BsAb recognizes a tumor-associated antigen (TAA) that is expressed on the surface of tumor cells, while the other arm recognizes a payload that is conjugated to a small molecule, such as digoxigenin (Dig), that serves as a linker. The payload can be a cytotoxic drug, an immunotoxin, a fluorescent dye, or any other agent that can exert a therapeutic or diagnostic effect. The BsAb acts as a carrier that transports the payload to the tumor cells via the TAA binding, and releases the payload inside the tumor cells after internalization and lysosomal degradation. This mechanism allows for selective delivery of potent agents to tumor cells, while minimizing the exposure and toxicity to normal cells. The BsAb can be designed with different formats and structures, such as IgG-scFv, Fab-scFv, or diabodies, depending on the desired properties and functions. The payload can be attached to the BsAb either covalently or non-covalently, depending on the stability and specificity of the linker. The TAA can be chosen from a variety of tumor-specific or tumor-enriched antigens, such as HER2, IGF1R, CD22, or LeY. The targeted payload delivery mechanism has been demonstrated in various preclinical and clinical studies, showing promising results in terms of efficacy and safety.
The features of the targeted payload delivery mechanism are mainly derived from the bispecific antibodies (BsAbs) that enable the selective and efficient delivery of potent agents to tumor cells or other target cells. Some of the main features are:
High efficiency: The BsAbs can bind to both the tumor-associated antigen (TAA) and the payload with high specificity and affinity, ensuring a high degree of targeting and uptake by the tumor cells. The BsAbs can also release the payload inside the tumor cells after lysosomal degradation, maximizing the intracellular delivery and activity of the payload. The BsAbs can also be designed with different formats and structures to optimize their pharmacokinetics, stability, and functionality.
High selectivity: The BsAbs can discriminate between tumor cells and normal cells based on the expression level and pattern of the TAA, reducing the off-target effects and toxicity of the payload. The BsAbs can also be combined with different payloads that have different modes of action and mechanisms of resistance, increasing the therapeutic window and overcoming tumor heterogeneity.
Low toxicity: The BsAbs can minimize the exposure of normal tissues and organs to the payload, as the payload is conjugated to a small molecule linker that is uncharged and inert in circulation. The payload is only activated when it is released inside the tumor cells after BsAb-mediated internalization and degradation. The payload can also be chosen from a variety of agents that have low systemic toxicity or immunogenicity, such as cytotoxic drugs, immunotoxins, fluorescent dyes, or nanoparticles.
Low resistance: The BsAbs can overcome the resistance mechanisms that limit the efficacy of conventional monoclonal antibodies or ADCs, such as antigen downregulation, antigen mutation, or efflux pumps. The BsAbs can also target multiple TAAs simultaneously or sequentially, preventing the escape or adaptation of tumor cells. The BsAbs can also deliver payloads that have multiple targets or mechanisms of action, such as duostatin-3, which disrupts microtubules by binding to both tubulin and kinesin.
The application of targeted payload delivery mechanism in cancer therapy or other fields is based on the idea that bispecific antibodies (BsAbs) can selectively deliver potent agents to tumor cells or other target cells, while sparing normal cells from the adverse effects. This idea has been explored in various preclinical and clinical studies, showing promising results and potential advantages over conventional therapies.
Table 1. Examples of BsAbs for Targeted Payload Delivery
| BsAb | TAA | Payload | Application |
|---|---|---|---|
| Blinatumomab | CD19 on B-cell malignancies | CD3 on T cells | Cancer therapy for ALL and DLBCL |
| Emicizumab | Factor IXa and factor X | Factor VIII mimetic | Hemophilia A prevention |
| Duostatin-3 | HER2 on breast cancer cells | Dig on microtubule-disrupting agent | Cancer therapy for HER2-positive breast cancer |
These applications demonstrate the versatility and feasibility of BsAbs for targeted payload delivery in various fields, especially in cancer therapy. However, there are also some challenges and limitations that need to be addressed, such as the optimal design and format of BsAbs, the selection and conjugation of payloads, the stability and pharmacokinetics of BsAb-payload complexes, the potential immunogenicity and toxicity of BsAbs or payloads, and the regulatory and ethical issues of BsAb-based therapies. Therefore, further research and development are needed to overcome these challenges and improve the efficacy and safety of BsAbs for targeted payload delivery.
References
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