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Published on: May 6, 2019
Fc-competent multispecific PDL-1/TIGIT/LAG-3 antibodies potentiate superior anti-tumor T cell response
Riyao Yang1, Su Huang1, Cai Huang1
1Ab Therapeutics Inc., 3541 Investment Blvd., Suite 2, Hayward, CA, 94545, USA.
Abstract:
The landscape of current cancer immunotherapy is dominated by antibodies targeting PD-1/PD-L1 and CTLA-4 that have transformed cancer therapy, yet their efficacy is limited by primary and acquired resistance. The blockade of additional immune checkpoints, especially TIGIT and LAG-3, has been extensively explored, but so far only a LAG-3 antibody has been approved for combination with nivolumab to treat unresectable or metastatic melanoma. Here we report the development of a PDL1 × TIGIT bi-specific antibody (bsAb) GB265, a PDL1 × LAG3 bsAb GB266, and a PDL1 × TIGIT × LAG3 tri-specific antibody (tsAb) GB266T, all with intact Fc function. In in vitro cell-based assays, these antibodies promote greater T cell expansion and tumor cell killing than benchmark antibodies and antibody combinations in an Fc-dependent manner, likely by facilitating T cell interactions (bridging) with cancer cells and monocytes, in addition to blocking immune checkpoints. In animal models, GB265 and GB266T antibodies outperformed benchmarks in tumor suppression. This study demonstrates the potential of a new generation of multispecific checkpoint inhibitors to overcome resistance to current monospecific checkpoint antibodies or their combinations for the treatment of human cancers.
Insights
New multi-specific antibodies targeting PD-L1, TIGIT, and LAG-3 show enhanced T cell activity and tumor suppression, offering a promising approach to overcome resistance in cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Current cancer immunotherapies like PD-1/PD-L1 and CTLA-4 antibodies have limitations due to primary and acquired resistance.
- While TIGIT and LAG-3 checkpoints are explored, only one LAG-3 antibody is approved in combination therapy.
- There is a need for novel strategies to enhance the efficacy of immune checkpoint blockade.
Purpose of the Study:
- To develop novel multi-specific antibodies targeting PD-L1, TIGIT, and LAG-3.
- To evaluate the efficacy of these novel antibodies in vitro and in vivo.
- To assess the potential of these agents to overcome resistance to existing immunotherapies.
Main Methods:
- Development of PD-L1 × TIGIT bi-specific antibody (GB265), PD-L1 × LAG3 bi-specific antibody (GB266), and PD-L1 × TIGIT × LAG3 tri-specific antibody (GB266T).
- In vitro cell-based assays to assess T cell expansion and tumor cell killing.
- In vivo studies using animal models to evaluate tumor suppression.
Main Results:
- The developed multi-specific antibodies demonstrated enhanced T cell expansion and tumor cell killing compared to benchmark antibodies.
- Fc-dependent mechanisms, including T cell-cancer cell and T cell-monocyte bridging, were implicated in the enhanced activity.
- GB265 and GB266T showed superior tumor suppression in animal models compared to benchmarks.
Conclusions:
- Multi-specific checkpoint inhibitors targeting PD-L1, TIGIT, and LAG-3 represent a new generation of cancer therapeutics.
- These novel antibodies have the potential to overcome resistance to current monospecific checkpoint inhibitors and their combinations.
- Further development of these agents could significantly improve treatment outcomes for various human cancers.
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