Abstract
Building upon the resounding therapeutic success of monoclonal antibodies, and supported by accelerating progress in engineering methods, the field of multispecific therapeutic antibodies is growing rapidly. Over 140 different molecules are currently in clinical testing, with excellent results in recent phase 1–3 clinical trials for several of them. Multivalent bispecific IgG-modified formats predominate today, with a clear tendency for more target antigens and further increased valency in newer constructs. The strategies to augment anticancer efficacy are currently equally divided between disruption of multiple surface antigens, and additional redirection of cytotoxic T or NK lymphocytes against the tumor. Both effects complement other modern modalities, such as tyrosine kinase inhibitors and adoptive cell therapies, with which multispecifics are increasingly applied in combination or merged, for example, in the form of antibody producing CAR-T cells and oncolytics. While mainly focused on B-cell malignancies early on, the contemporary multispecific antibody sector accommodates twice as many trials against solid compared to hematologic cancers. An exciting emerging prospect is the targeting of intracellular neoantigens using T-cell receptor (TCR) fusion proteins or TCR-mimic antibody fragments. Considering the fact that introduction of PD-(L)1 inhibitors only a few years ago has already facilitated 5-year survival rates of 30–50% for per se highly lethal neoplasms, such as metastatic melanoma and non-small-cell lung carcinoma, the upcoming enforcement of current treatments with “next-generation” immunotherapeutics, offers a justified hope for the cure of some advanced cancers in the near future.
Highlights
The tortuous, 2.5 billion-years-long path from immunoglobulin (Ig)-like domains of archaeal flagellins to the antibodies (Ab) of jawed vertebrates is one of the most intriguing discoveries in evolutionary biology [1,2,3]
Impressive are the accomplishments of modern genetic engineering, whose further variation of basic Ig building blocks could produce over 40 different molecular formats of therapeutic antibodies during the last two decades [4]
The concept that antibodies could be used as “magic bullets” against human maladies dates back to their discovery in the late 19th century [6] and the gradual recognition that they can bind a virtually unlimited number of antigens with a high specificity and affinity [7]. It was not until discovery of the “hybridoma” technology in 1975 [8], complemented by various humanization techniques a few years later [9], that scientists managed to harness this power: monoclonal antibodies could be produced in large quantities after injecting a mouse with the desired antigen, and fusing the respective splenocytes with suitable myeloma cell lines [10]
Summary
The tortuous, 2.5 billion-years-long path from immunoglobulin (Ig)-like domains of archaeal flagellins to the antibodies (Ab) of jawed vertebrates is one of the most intriguing discoveries in evolutionary biology [1,2,3]. The concept that antibodies could be used as “magic bullets” against human maladies dates back to their discovery in the late 19th century [6] and the gradual recognition that they can bind a virtually unlimited number of antigens with a high specificity and affinity [7] It was not until discovery of the “hybridoma” technology in 1975 [8], complemented by various humanization techniques a few years later [9], that scientists managed to harness this power: monoclonal antibodies could be produced in large quantities after injecting a mouse (later, rat or other mammal) with the desired antigen, and fusing the respective splenocytes with suitable myeloma cell lines [10].
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