Bi- and trispecific immune cell engagers for immunotherapy of hematological malignancies

Abstract

Immune cell engagers are engineered antibodies with at least one arm binding a tumor-associated antigen and at least another one directed against an activating receptor in immune effector cells: CD3 for recruitment of T cells and CD16a for NK cells. The first T cell engager (the anti-CD19 blinatumomab) was approved by the FDA in 2014, but no other one hit the market until 2022. Now the field is gaining momentum, with three approvals in 2022 and 2023 (as of May): the anti-CD20 × anti-CD3 mosunetuzumab and epcoritamab and the anti-B cell maturation antigen (BCMA) × anti-CD3 teclistamab, and another three molecules in regulatory review. T cell engagers will likely revolutionize the treatment of hematological malignancies in the short term, as they are considerably more potent than conventional monoclonal antibodies recognizing the same tumor antigens. The field is thriving, with a plethora of different formats and targets, and around 100 bispecific T cell engagers more are already in clinical trials. Bispecific NK cell engagers are also in early-stage clinical studies and may offer similar efficacy with milder side effects. Trispecific antibodies (engaging either T cell or NK cell receptors) raise the game even further with a third binding moiety, which allows either the targeting of an additional tumor-associated antigen to increase specificity and avoid immune escape or the targeting of additional costimulatory receptors on the immune cell to improve its effector functions. Altogether, these engineered molecules may change the paradigm of treatment for relapsed or refractory hematological malignancies.

The clinical regimens and cell membrane camouflaged nanodrug delivery systems in hematologic malignancies treatment

“…Alternatively, it can target additional costimulatory receptors on immune cells, thereby enhancing their effector functions ( Liu D. et al, 2022 ). Until now, around 100 bispecific T cell engagers are in clinical trials, and NK cell engagers and TsAbs are currently undergoing early-stage clinical studies because of late starting ( Tapia-Galisteo et al, 2023 ).…”

Immunotherapy: a promising approach for glioma treatment

“…In recent years, bispecific antibodies (BsAbs) have emerged as a promising therapeutic approach in oncology, with notable applications in cancer treatment ( 94 , 95 ). Unlike conventional antibodies, BsAbs possess two distinct antigen-binding sites, allowing them to function through various mechanisms, including immune cell activation, co-inhibitory receptor blockade, co-stimulatory molecule triggering, signaling pathway suppression, and collaborative targeting of cancer-related antigens ( 96 ).…”

“…Unlike conventional antibodies, BsAbs possess two distinct antigen-binding sites, allowing them to function through various mechanisms, including immune cell activation, co-inhibitory receptor blockade, co-stimulatory molecule triggering, signaling pathway suppression, and collaborative targeting of cancer-related antigens ( 96 ). Several BsAbs, such as blinatumomab, mosunetuzumab, teclistamab, epcoritamab, and glofitamab, have gained approval for cancer treatment ( 95 ). However, the development of BsAbs for glioma therapy has been relatively slow, with most investigations confined to preclinical stages ( 97 – 101 ).…”

Talquetamab: A promising immunotherapy for multiple myeloma

“…Specific adverse events (AEs) included dysgeusia, skin-related AEs, primarily low-grade nail disorders. 5 It also caused the development of grade 1 or 2 CRS in about 75% of the patients, and infections in more than half of them and few hematological AEs were also reported. 4 The TRiMM-2 study is assessing several talquetamabbased combinations.…”