Payload delivery

Backgrounds

An interesting application of bispecific antibodies (BsAbs) is the delivery of payloads such as drugs, radioactive tags, and nanoparticles. Once the unbound bispecific molecules are cleared from the blood, the payload is administered, making BsAbs an ideal therapeutic delivery system for binding both cell-surface antigens and payload. Particularly in oncology, where antibodies can bind to cytotoxic entities with limited selectivity, bispecific molecules can be used to enrich the payload at the tumor site. Bispecific molecules can bind different haptenylated payloads, and vice versa, a payload can be linked to hapten bispecific molecules with different specificities. Thus, the targeting system is highly general. A well-known hapten is digoxin (Dig).

BsAbs for Payload Delivery Therapy

Dig, as a hapten, can be used as a payload scaffold to perform some cytotoxic fractions. BsAbs targeting cell membrane antigens and DIG are generated for the targeted delivery of payloads. Since DIG-BsAbs also efficiently capture digoxigeninylated compounds under physiological conditions, administration of uncharged Dig BsAbs followed by application of Dig payloads, respectively, is sufficient to achieve antibody-mediated targeting in vitro and in vivo. Introducing small interfering RNA (siRNA) into tumor cells and knocking down some important genes is also a promising method for cancer treatment. Hapten-BsAbs are also an effective siRNA delivery system. Targeting small cells loaded with chemotherapeutic drugs by BsAbs against cancer cell membrane antigens results in cellular endocytosis, intracellular degradation, and drug release. A phase I clinical study of BsAb-mediated paclitaxel minicells targeting EGFR has been initiated, and the results indicate that this small-cell delivery system is well tolerated and safe in patients and shows modest clinical efficacy.

Fig.1 Mechanism of action of BsAb: delivery of payloads & targeting tumor-associated signaling pathways.¹

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Reference

1. Guo, Xiaohan, et al. "Revolutionizing cancer immunotherapy: unleashing the potential of bispecific antibodies for targeted treatment." Frontiers in Immunology 14 (2023): 1291836.