Recent Advances in the Molecular Design and Applications of Multispecific Biotherapeutics

Abstract

Recombinant protein-based biotherapeutics drugs have transformed clinical pipelines of the biopharmaceutical industry since the launch of recombinant insulin nearly four decades ago. These biologic drugs are structurally more complex than small molecules, and yet share a similar principle for rational drug discovery and development: That is to start with a pre-defined target and follow with the functional modulation with a therapeutic agent. Despite these tremendous successes, this “one target one drug” paradigm has been challenged by complex disease mechanisms that involve multiple pathways and demand new therapeutic routes. A rapidly evolving wave of multispecific biotherapeutics is coming into focus. These new therapeutic drugs are able to engage two or more protein targets via distinct binding interfaces with or without the chemical conjugation to large or small molecules. They possess the potential to not only address disease intricacy but also exploit new therapeutic mechanisms and assess undruggable targets for conventional monospecific biologics. This review focuses on the recent advances in molecular design and applications of major classes of multispecific biotherapeutics drugs, which include immune cells engagers, antibody-drug conjugates, multispecific tetherbodies, biologic matchmakers, and small-scaffold multispecific modalities. Challenges posed by the multispecific biotherapeutics drugs and their future outlooks are also discussed.

Bispecific T Cell Engagers for the Treatment of Multiple Myeloma: Achievements and Challenges

“…The use of biotechnology such as nanomaterials has the potential to circumvent limitations while maintaining or improving the current advantages. Future directions for development of TCEs for MM should include: (1) advancing the investigation of CS1 (SLAMF7) as a TCE target in vivo and in clinical trials based on promising results recently [91,103]; (2) focusing on development of trispecific TCEs to overcome antigen-less tumor relapse and treatment resistance; (3) expanding TCE technology to engage non-conventional T cells such as NK-and γδ T cells [104,105]; (4) interrogating TCE combination therapy with current therapies such as autologous stem cell transplant, daratumumab, and/or checkpoint inhibitors; (5) exploring novel formats such as nanomaterial, camelid nanobody, tandem diabody, dual-affinity retargeting antibody [106][107][108]. Taken together, TCE immunotherapy has immense potential and can be further improved as an efficient treatment for the clearance of MM and other cancers.…”

Applying Synthetic Biology with Rational Design to Nature’s Greatest Challenges: Bioengineering Immunotherapeutics for the Treatment of Glioblastoma

“…Engineered molecules can be devised to avoid this limitation through conformations that do not require disulfide bonds. For example, Monobodies and Fynomers are scaffolds that inherently do not require disulfide bonds for their stability [39] and Affibodies are known to be incredibly stable across a wide range of environments. Protein-polymer conjugates have been designed to alter the temperature and pH dependence of activity, solubility, and stability [38].…”

“…A multitude of immune cell types are implicated in tumor immunoevasion or anti-tumor activity, including CD8 + T cells, CD4 + helper T cells, dendritic cells, macrophages, and B cells, necessitating thoughtful, multipronged immunotherapeutic strategies [23]. Additionally, the cancer-immunity cycle progresses through many stages marked by various patterns of expression, including the preparatory phase (tumor antigen release and presentation, T-cell priming and activation) and effector stage (cytotoxic T lymphocyte trafficking, infiltration, recognition, and killing), that take place in multiple locations, including the tumor microenvironment and draining lymph nodes [39].…”

“…Engineering therapeutics with multispecificity to target different pathways is one promising strategy consisting of two major categories, non-obligate and obligate multispecific [39,40]. Non-obligate multispecific therapeutics are recombinant antibody-based molecules that simultaneously modulate two or more signaling pathways when binding their targets and are similarly efficacious to a mixture of distinct antibodies.…”

“…Choi et al, demonstrated CAR T cells secreting BiTEs against epidermal growth factor receptor (EGFR) that additionally interact with circulating T cells and allow their enhanced trafficking to the tumor site [41]. Other examples include antibody-drug conjugates, tertherbodies, and biologic matchmaker drugs that exert their function through binding multiple targets simultaneously [39].…”