Overview of Bispecific Antibodies Conjugates

Antibody-based therapies are one of the most promising approaches for cancer treatment, as they can exploit the specificity and diversity of antibodies to recognize and eliminate tumor cells. Among the various types of antibody-based therapies, antibody-drug conjugates (ADCs) and bispecific antibodies (bsAbs) have attracted considerable attention in recent years. ADCs can achieve high specificity and potency, as well as reduced systemic toxicity, compared to conventional chemotherapy. However, ADCs also face some challenges, such as drug resistance, non-specific binding, and complex manufacturing. BsAbs can overcome some limitations of conventional mAbs, such as heterogeneity and escape of tumor cells, low expression of TAAs, and poor penetration into solid tumors. However, bsAbs also have some drawbacks, such as immunogenicity, instability, and difficult production. To combine the advantages of ADCs and bsAbs and overcome their limitations, a new type of antibody-based therapy has emerged, namely bispecific antibody conjugates (BACs). BACs are hybrid molecules that consist of two different antibodies, or antibody fragments, that are conjugated to each other and carry a cytotoxic payload. BACs can target two antigens simultaneously and deliver the payload to the tumor site, resulting in enhanced selectivity and efficacy. BACs can also overcome some of the challenges of ADCs and bsAbs, such as drug resistance, non-specific toxicity, and complex manufacturing.

Overview of IgG-IgG

IgG-IgG bispecific antibody conjugates are a type of engineered antibody that can bind to two different antigens simultaneously. They have the same size and structure as a conventional IgG antibody, but they have different heavy and light chains in each arm of the Y-shaped molecule. This allows them to target multiple pathways or cells involved in diseases such as cancer. For example, they can block two receptors on the same tumor cell, or they can recruit immune cells to kill tumor cells by binding to both CD3 and a tumor antigen. IgG-IgG bispecific antibody conjugates can also be linked to cytotoxic drugs, such as pyrrolobenzodiazepine (PBD), to deliver them selectively to the tumor cells and enhance their therapeutic activity. IgG-IgG bispecific antibody conjugates are generated by modifying the constant regions of the heavy and light chains to prevent unwanted pairing and homodimerization. Various methods have been developed to achieve this, such as introducing mutations, knobs-into-holes, charge pairs, or leucine zippers. IgG-IgG bispecific antibody conjugates have the advantage of retaining the biophysical properties of a regular IgG, such as stability, half-life, and tissue penetration. They also have the potential to reduce drug resistance and off-target toxicity. Several IgG-IgG bispecific antibody conjugates are in clinical development for various indications.

Overview of Cov-X-Body

Cov-X-Body is a novel design method for bispecific antibody conjugates, which attaches small molecule drugs to the lysine residues of two Fab arms, extending the half-life of the small molecules. The first clinical trial of CVX-241, which used this method to link VEGF and Ang2 small molecule inhibitors to the Fab arms, was terminated due to its unclear efficacy. Cov-X-Body is a unique class of fusion proteins that combines a recombinant humanized monoclonal antibody and two anti-angiogenic peptides. The mechanism of action of Cov-X-Body is to block the angiogenic signaling pathway by the anti-angiogenic peptides on the Fab arms, thereby inhibiting the vascular supply and growth of tumors. Cov-X-Body can also enhance the immune recognition and killing of tumor cells by binding to specific antigens on the tumor cell surface by the antibody part on the Fab arms. Currently, Cov-X-Body is undergoing other clinical trials to evaluate its safety and efficacy in treating different types of solid tumors.

Overview of scFv1-PEG-scFv2

scFv1-PEG-scFv2 is composed of two single-chain variable fragments (scFv) and a polyethylene glycol (PEG)-containing cross-linker. This BsAb can recognize two different antigens at the same time and has three reactive groups—two scFv reactive groups and one PEG reactive group. Introducing PEG into cross-linkers has many advantages, such as reducing the risk of antibody inactivation, reducing product heterogeneity, and extending the half-life of antibodies. In addition to PEG, other molecules, such as antibody fragments, peptides, siRNA, toxic drugs, or fluorescein, can also be introduced to increase the functionality of BsAb. scFv1-PEG-scFv2 BsAb is an innovative BsAb format that can be used for research and treatment in cancer, immunology, hematology and other fields.

References

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