CRS Generated from Bispecific T Cell Engagers (BiTEs)

CRE_Bispecific_Antibody_CRS_and_ICANS_Neurotoxicity_Guidance_Feb2024 51899285fnl_Immunotoxic Potential of PharmaceuticalsWe are considering Bispecific T cell engagers (BiTEs) [1] as an alternative to a CAR T driven cytokine release as an immunotherapy focused DDT. BiTEs are monoclonal antibodies engineered to have one arm that recognizes a T Cell surface antigen and another that recognizes a tumor antigen.

There are number of BiTEs on the market for B lymphomas. The two arms bring bring T Cells and tumor cells in close proximity enabling the T cells to lyse the tumor cell.  Just like CAR T tumor cell killing, this frequently generates cytokine release syndrome (CRS) followed in some cases by the potentially more serious Immune effector cell-associated neurotoxicity syndrome (ICANS). Like CAR T therapies, BiTE prescriptions come with ‘boxed’ warnings for both CRS and ICANS. Boxed warnings concern the most serious side effects of a drugs-. Here are two examples …

There are two strategic reasons why I think we should generate CRS from BiTEs rather than CAR T.

First is a very important new development in the regulatory world: The FDA just published (April 10, 2025) the FDA Roadmap to Reducing Animal Testing in Preclinical Safety Studies. This was accompanied by an announcement that the FDA will immediately prioritize non-animal models for the study of monoclonal antibody drugs (mAbs). BiTES are mAbs.

The second reason is the relative simplicity of generating CRS in the lab with BiTES. This paper describes a whole blood assay that generates full spectrum CRS [2] by simply adding a commercially available drug to healthy blood [2]. There are likely ways for generating CRS using CAR T in whole blood, but obtaining CAR T is not as easy as obtaining BiTES. The inspiration for this work – Minsoo Kim’s studies showing CRS generation on lung vascular model – are simulating solid tissue generation of CRS. This is going to be highly donor specific. At least the two B lymphoma examples above are simply cross linking T cells with standard B-cell surface markers (CD19 and CD20). This will not a patient specific assay drug.  The simplicity of generation CRS means we can focus our attention on ICANS – which is effectively modeled in the sepsis focused BBB models in our (McGrath) lab.

There is FDA Guidance on BiTES (although not as extensive as CAR T?). There is also federal clinical guidance from the VA that describes management of CRS and ICANS for 8 different BiTEs.
[1] Herrera M, Pretelli G, Desai J, Garralda E, Siu LL, Steiner TM, Au L. Bispecific antibodies: advancing precision oncology. Trends Cancer. 2024;10(10):893-919.

[2] Leclercq-Cohen G, Steinhoff N, Alberti Servera L, Nassiri S, Danilin S, Piccione E, Yanguez E, Husser T, Herter S, Schmeing S, Gerber P, Schwalie P, Sam J, Briner S, Jenni S, Bianchi R, Biehl M, Cremasco F, Apostolopoulou K, Haegel H, Klein C, Umana P, Bacac M. Dissecting the Mechanisms Underlying the Cytokine Release Syndrome (CRS) Mediated by T-Cell Bispecific Antibodies. Clin Cancer Res. 2023;29(21):4449-63.