Type: Oral
Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational III
Hematology Disease Topics & Pathways:
Biological therapies, Bispecific Antibody Therapy, drug development, Therapies, Immunotherapy
In order to mimic antigen escape due to target downregulation post monotargeted therapies, ISB 2001 was evaluated in vitro comparing MM cell lines expressing either low levels of both CD38 and BCMA (KMS-12-BM), or high levels of CD38 and very low levels of BCMA (MOLP-8). Compared to monospecific T cell engagers, the binding of ISB 2001 to these cells was strongly increased due to avidity, while retaining reduced affinity to cells devoid of either CD38 or BCMA. ISB 2001 exhibited potent killing with EC50 ranging from 0.4 to 1.2 pM in different cell lines, which was 3 – 41-fold superior to that of EM801, a BCMA-targeted T cell engager7. The potency of ISB 2001 was superior to the combination of the CD38-specific and BCMA-specific T cell engagers constructed with the same binding domains, demonstrating the advantage of avidity augmentation when binding to CD38 and BCMA simultaneously. ISB 2001 was only modestly affected by soluble BCMA or APRIL when compared to EM801, demonstrating killing at 3 pM (EC50) in the presence of these soluble factors.
Given the wide expression of CD38 on healthy immune cells, we evaluated whether the avidity induction enabled by the dual targeting could preferentially target MM cells while sparing normal immune cells. ISB 2001 induced low T cell activation and cytokine secretion in the absence of tumor cells, similar to EM801. This was in line with low binding to T cells (apparent cell-based affinity approx. 150 nM) and minimal binding to circulating CD38+ BCMA- healthy cells, indicative of low on-target off-tumour activity of ISB 2001.
ISB 2001 showed potent anti-tumor activity in bone marrow aspirates of MM patients and in blood samples from plasma cell leukemia patients, indicating the ability of ISB 2001 to leverage its cytotoxic properties with available immune cells.
The half-life of 7 days for ISB 2001 was determined in a preclinical study in human FcRn receptor-expressing TG32 mice. When evaluated in a therapeutic PBMC-humanized mouse model subcutaneously engrafted with KMS-12-BM cells, ISB 2001 was able to induce tumor regression at doses of 0.1 mg/kg. Even at doses as low as 0.02 mg/kg, ISB 2001 demonstrated significant growth inhibition. The in vivo efficacy was associated with T cell infiltration, T cell activation and cytokine release at the tumour site but not systemically.
As reported here, ISB 2001 data support future clinical development as a potent treatment of MM through co-targeting CD38 and BCMA. Based on the specific dual targeting of MM cells, significant benefit is anticipated for relapsed/refractory patients who may experience tumor escape through target downregulation mechanisms. Preparations for the initiation of a Phase 1 clinical trial are ongoing.
References
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Disclosures: Pihlgren: Ichnos Science: Current Employment; AC immune: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Hall: Ichnos Science: Current Employment. Carretero: Ichnos Science: Current Employment. Estoppey: Ichnos Sciences: Current Employment. Drake: Ichnos Science: Current Employment. Pais: Ichnos Science: Current Employment. Loyau: Ichnos Science: Current Employment. Berret: Ichnos Science: Current Employment. Gruber: Ichnos Science: Current Employment. Suere: Ichnos Science: Current Employment. Schnorhk: Ichnos Science: Current Employment. Nallet: Ichnos Science: Current Employment. Pouleau: Ichnos Science: Current Employment. Chimen: Ichnos Sciences: Current Employment. Macoin: Ichnos Science: Current Employment. Stainnack: Ichnos Science: Current Employment. Monney: Ichnos Science: Current Employment. Delachat: Ichnos Science: Current Employment. Dreyfus: Ichnos Science: Current Employment. Konto: Ichnos Science: Current Employment. Dyson: Ichnos Science: Current Employment. Blein: Ichnos Science: Ended employment in the past 24 months. Mbow: Ichnos Science: Ended employment in the past 24 months. Wood: Ichnos Science: Ended employment in the past 24 months. Srivastava: Ichnos Science: Current Employment. Zhukovsky: Ichnos Science: Current Employment. Perro: Ichnos Science: Current Employment.
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