Development of a novel bispecific T-cell engager targeting ILT3

The Multiple Myeloma Hub is pleased to summarize the work presented by Francesco Di Meo at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition, which described the challenges in B-cell maturation antigen (BCMA) therapy, as well as the development of a novel bispecific T-cell engager with promising antitumor activity in multiple myeloma cell lines and animal models.¹

Challenges for BCMA therapy in multiple myeloma¹

• Cells with low or no BCMA expression can evade treatment, which leads to the expansion of resistant clones.
• BCMA expression can be downregulated as a mechanism of tumor resistance.
• BCMA is expressed on normal tissues; therefore BCMA-targeted therapy can lead to toxicity.
• Relapse after BCMA-targeted chimeric antigen receptor T-cell therapy is common.

Development and evaluation of a novel bispecific T-cell engager¹

Figure 1. Process of developing an MM cell-targeting BiTE*

BCMA, B-cell maturation antigen; BiTE, bispecific T-cell engager; Fab, fragment antigen-binding; Fc,  fragment crystallizable; MM, multiple myeloma; RNAseq, RNA sequencing; scFv, single-chain variable fragment.
*Data from Di Meo.¹

Figure 2. Stepwise selection process of potential BiTE target*

BiTE, bispecific T-cell engager; HSC, hematopoietic stem cell; MM, multiple myeloma; MS, mass spectrometry; pt, patient; R/R, relapsed/refractory; RNAseq, RNA sequencing.
*Adapted from Di Meo.¹

Figure 3. Structure of ILT3-targeting BiTE* 

BiTE, bispecific T-cell engager; Fab, fragment antigen-binding; Fc, fragment crystallizable; IgG, immunoglobulin G, MM, multiple myeloma; scFv, single-chain variable fragment.
*Adapted from Di Meo.¹ Created with BioRender.com.

Conclusion

Based on the efficacy and antitumor activity of a novel bispecific T-cell engager in MM cell lines and murine models, ILT3 is a promising target for future MM therapies. In-human clinical trials are under development.