Disease indication – multiple myeloma
Drug format – antibodies conjugated to nanoparticles for T-cell immunotherapy
Drug class – improved delivery platform
Research stage and Preliminary data:
- Efficacy – CD38/CD3 nanoTCEs significantly prolonged survival (100% survival at 40 days) and decreased tumor burden in a mouse model of MM
- Pharmacokinetics – T1/2 of 36 hours for NanoTCEs in healthy mice (compared to 2.1 hrs for classic BiTEs)
In vitro proof of concept – in a MM cell line: NanoMuTEs and NanoTCEs both demonstrated specific binding and caused T-cell induced cell lysis; NanoMuTE’s had improved binding and improved T-cell activation over NanoTCEs
Target – CD3 for T-cell engagement and multiple myeloma targets CD38, BCMA and CS1 tested to date (could be extended to additional targets)
Multiple myeloma (MM) is a heterogeneous disease, with cancer cells expressing a large and dynamic repertoire of surface antigens. However, current T-cell immunotherapy strategies for MM (chimeric antigen receptor-T, “CAR-T”, and bispecific T-cell engagers, “BiTEs”) target only one antigen on the cancer cells. Over time, the non-targeted cells (known as antigen-less variants) can proliferate which can and lead to relapse after treatment. This so-called “loss of antigen” occurs in 44% of patients that respond to initial multiple myeloma therapy.
Additional challenges of current T-cell immunotherapy include the short half-life of BiTE molecules and the expensive and labor intensive engineering of autologous patient CAR T-cells.
Keywords – T-cell immunotherapy, T-cell enhancer, multiple myeloma, nanoparticle, NanoTCE, NanoMuTE, bispecific, multispecific, antibody, liposome
Mode of action:
Schematic of NanoTCEs and NanoMuTEs: NanoTCEs (first 3 figures) are liposomal nanoparticles conjugated to a cancer-targeting antibody (e.g., BCMA, CS1, CD38) and T-cell engaging antibody (CD3). NanoMuTEs (far right) are an extension of NanoTCEs, with three or more cancer-targeting antibodies designed for efficacy against heterogeneous cancer cells.
NanoTCEs (nanoparticle bispecific T-cell engager) and NanoMuTEs (nanoparticle multivalent T-cell engager) are liposome nanoparticles chemically conjugated to two or more antibodies – one (or more) antibody to target the cancer cells and the other antibody to engage and activate the T-cell. This immunotherapy system is designed to target a range of variants of the multiple myeloma with a single off-the-shelf agent. This is expected to provide enhanced antigen recognition to redirect the patient’s immune system to fight the cancer while avoiding relapse from loss of antigen.
The nanoparticle-based system also improves the pharmacokinetics over traditional BiTE therapy.
- Broad targeting – enhanced antigen recognition compared to current T-cell therapies
- designed to activate T-cells against heterogeneous cancer cells with a variety of cell surface antigens
- easily add antibodies to multiple targets to NanoMuTE particle
- Improved pharmacokinetics – compared to conventional BiTE antibodies, NanoTCEs have longer biodistribution and half-life (36 hrs. vs. 2.1 hrs.)
- Off-the-shelf – unlike CAR T-cell immunotherapy (which requires individual preparation of genetically engineered autologous cells for each patient), a standard NanoTCE or NanoMuTE agent can be used for any patient who’s cancer expresses the targeted marker
- Advantages of nanoparticles:
- simple, low cost, scalable production
- non-toxic liposome material
Patents – Provisional patent application filed
Website – Azab Lab