Regression of EGFR positive established solid tumors in mice with the conditionally active T cell engager TAK-186
Danielle E Dettling1, Eilene Kwok2, Lucy Quach2
1Oncology Drug Development Unit, Takeda Development Centers America, Inc (TDCA), Lexington, Massachusetts, USA danielle.dettling@alaunusbio.com.
Background:
Despite clinical success with T cell engagers (TCEs) targeting hematological malignancies, achieving a safe and efficacious dose in patients with solid tumors remains challenging. Due to potency, low levels of target antigen expression on normal tissues may not be tolerated. To overcome this, we engineered a novel conditionally active TCE design called COBRA (Conditional Bispecific Redirected Activation). Administered as prodrugs, COBRAs bind to cell surface antigens on both normal and tumor tissues but are preferentially activated within the tumor microenvironment.
Methods:
A COBRA was engineered to target EGFR, TAK-186. The potency of precleaved TAK-186 relative to a non-cleavable control was assessed in vitro. Mice bearing established solid tumors expressing a range of EGFR levels were administered a single bolus of human T cells, and concurrently treated with TAK-186 and associated controls intravenously. We assessed the plasma and tumor exposure of intact and cleaved TAK-186.
Results:
TAK-186 shows potent redirected T cell killing of antigen expressing tumor cells. In vivo efficacy studies demonstrate regressions of established solid tumors, dependent on intratumoral COBRA cleavage. Pharmacokinetic studies reveal TAK-186 is stable in circulation, but once activated is rapidly cleared due to loss of its albumin-binding half-life extension domain.
Conclusions:
The studies shown support the advancement of TAK-186, and the pursuit of additional COBRA TCEs for the treatment of solid tumors.
Insights
A novel conditionally active T cell engager (TCE), COBRA, shows promise for solid tumors. This prodrug design, TAK-186, is activated in the tumor microenvironment, leading to potent T cell killing and tumor regression.
Area of Science:
- Oncology
- Immunotherapy
- Drug Development
Background:
- T cell engagers (TCEs) show success in blood cancers but face challenges in solid tumors due to potential toxicity on normal tissues.
- Target antigen expression on normal tissues can limit safe dosing of potent TCEs in solid tumors.
- A novel conditionally active TCE design, COBRA (Conditional Bispecific Redirected Activation), has been engineered to overcome these limitations.
Purpose of the Study:
- To engineer and evaluate a novel conditionally active TCE, COBRA, for solid tumor treatment.
- To assess the efficacy and pharmacokinetics of a COBRA TCE targeting EGFR, named TAK-186.
- To demonstrate tumor-specific activation and T cell-mediated killing by the COBRA design.
Main Methods:
- Engineered a COBRA TCE targeting EGFR, designated TAK-186, designed as a prodrug.
- Assessed the in vitro potency of precleaved TAK-186 compared to a non-cleavable control.
- Conducted in vivo studies in mice with solid tumors, administering human T cells and TAK-186, and analyzed plasma and tumor exposure.
Main Results:
- TAK-186 demonstrated potent, antigen-specific T cell-mediated tumor cell killing in vitro.
- In vivo studies showed regression of established solid tumors, dependent on intratumoral COBRA cleavage.
- Pharmacokinetic analysis indicated TAK-186 stability in circulation with rapid clearance upon activation in the tumor.
Conclusions:
- The COBRA TCE design, exemplified by TAK-186, supports advancement for solid tumor treatment.
- Conditional activation within the tumor microenvironment enhances safety and efficacy.
- Further development of COBRA TCEs is warranted for solid tumors.
