Bispecific Antibodies and Antibody–Drug Conjugates for Cancer Therapy: Technological Considerations

Abstract

The ability of monoclonal antibodies to specifically bind a target antigen and neutralize or stimulate its activity is the basis for the rapid growth and development of the therapeutic antibody field. In recent years, traditional immunoglobulin antibodies have been further engineered for better efficacy and safety, and technological developments in the field enabled the design and production of engineered antibodies capable of mediating therapeutic functions hitherto unattainable by conventional antibody formats. Representative of this newer generation of therapeutic antibody formats are bispecific antibodies and antibody–drug conjugates, each with several approved drugs and dozens more in the clinical development phase. In this review, the technological principles and challenges of bispecific antibodies and antibody–drug conjugates are discussed, with emphasis on clinically validated formats but also including recent developments in the fields, many of which are expected to significantly augment the current therapeutic arsenal against cancer and other diseases with unmet medical needs.

Bispecific antibodies targeting dual tumor-associated antigens in cancer therapy

“…Antibody–drug conjugate (ADC) therapeutics combine the targeting precision of an antibody with the cytotoxic activity of a highly potent cytotoxic payload by conjugation to mAbs. Once the drug conjugated antibodies bind the antigens on tumor cell surface, ADCs are internalized by receptor-mediated endocytosis, and the toxic payload is released (Shim 2020 ). In the apparent absence of tumor-specific mAb targets or because tumor-selective targets not always internalize well, BsAbs may provide improved options compared to monospecific antibody-based ADC for tumor-selective delivery of highly potent chemical payloads.…”

Recent Advances in the Molecular Design and Applications of Multispecific Biotherapeutics

“…Non-protein entities utilize small molecules and oligonucleotides to greatly broaden the mechanism of action and design versatilities of the multispecific biotherapeutics [6,[16][17][18][19]. They enable specific binding to intracellular drug targets such as those involved in replication and division of cells and DNAs.…”

“…Among them, there are three approved bispecific antibodies (catumaxomab (Removab TM ), blinatumomab (Blincyto ® ), emicizumab (Hemlibra ® )), one approved antibody binding fragment fusion with immunotoxin (Lumoxiti TM ), and nine approved antibody-drug conjugates (gemtuzumab ozogamicin (Mylotarg ® ), brentuximab vedotin (Adcetris ® ), ado-trastuzumab emtansine (Kadcyla ® ), inotuzumab ozogamicin (Besponsa ® ), enfortumab vedotin (Padcev TM ), fam-trastuzumab deruxtecan-nxki (Enhertu ® ), polatuzumab vedotin-piiq (Polivy TM ), belantamab mafodotin-blmf (Blenrep TM ), sacituzumab govitecan (Trodelvy TM )). These successes, along with nearly 200 multispecific biotherapeutic candidates in the clinical pipelines [3][4][5][6]10,[16][17][18][19][20][21][22][23][24][25][26][27][28], indicate that multispecific bio-therapeutics are promising molecules. However, discovering and developing them into an approved product is challenging and requires extensive efforts in engineering and development.…”

“…The topic of multispecific biotherapeutics represents a fast-growing field regarding formats, design strategies, and applications. A number of outstanding review articles have been written on this topic or related themes for the past few years [2][3][4][5][6][9][10][11][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. This review summarizes comprehensively the recent advances in molecular design and applications of the multispecific biotherapeutics from the early stages of research discovery to the late stages of clinical and regulatory development.…”

Facing the Challenges of Pharmaceutical Research Using Whispering Gallery Modes-Based Biosensors

“…Additionally, for kinetic analysis each binding pair should be tested empirically to evaluate the most suitable sitedirected immobilization method in order to control the density of binding sites on the sensor surface, as very high one might alter the KD and KA values. On the other hand, the increasing complexity of novel biotherapeutics has raised new challenges for functional characterization, as when compared to standard antibodies, bispecific antibodies require the consideration of two individual interactions [7]. Only a couple of technologies, including suspension array technology [8] or surface plasmon resonance (SPR) have been described for bi-functional characterization in one approach.…”