| Autor: |
Linda Crew, Zeyu Peng, Thomas O'Neill, James L. Boyer, Mark Z. Ma, Michael T. Murphy, Lawrence J. Thomas, Jeff Weidlick, Colleen Patterson, Russell A. Hammond, Diego Alvarado, Anna Wasiuk, April R. Baronas, Joel Goldstein, Laura Mills-Chen, Tibor Keler, Andrea Crocker, Jay S. Lillquist, Jenifer Widger, Laura Vitale, Ed Natoli, Collin Xia, Henry C. Marsh, Hugh Davis |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
Journal for ImmunoTherapy of Cancer. 9:A833-A833 |
| ISSN: |
2051-1426 |
| DOI: |
10.1136/jitc-2021-sitc2021.798 |
| Popis: |
BackgroundActivation of the ITIM-bearing ILT4/LILRB2 receptor by its cognate ligands (HLA-G and HLA Class I) has been postulated as a resistance mechanism for checkpoint blockade of PD-1 and CTLA-4. Dual inhibition of receptors that suppress myeloid and T cell compartments through the generation of bispecific antibodies (bsAbs) is a promising strategy to improve outcomes for patients whose tumors are resistant to checkpoint inhibition.MethodsWe describe the discovery and characterization of CDX-585 a bsAb developed from novel ILT4 and PD-1 antagonist mAbs that revert myeloid cell suppression by antagonizing ILT4 and activating T-cell responses through PD-1 inhibition. The bsAb was engineered as a tetravalent molecule using the PD-1 IgG1 mAb linked to scFv of the ILT4 mAb at the C-terminus of the heavy chain. A series of mutations were introduced in the Fc domain to eliminate Fcy receptor binding and increase affinity to the neonatal Fc receptor. CDX-585 has good biophysical characteristics and retains functional properties similar to, or better, than the parental mAbs.ResultsCDX-585 has sub-nanomolar affinity binding to ILT4 and PD-1 and is a potent competitor of their respective ligands. Primary cultures of human macrophages and dendritic cells treated with CDX-585 enhanced production of inflammatory cytokines/chemokines, which was further potentiated in the presence of toll like receptor activation with lipopolysaccharide (LPS). CDX-585 was particularly effective in promoting T cell activation as measured by mixed lymphocyte reactions, and in polarizing macrophages towards M1 based on their cytokine profile. Pilot studies in mice and cynomolgus macaques confirmed a favorable pharmacokinetic profile without adverse effects of treatment noted in clinical observations or clinical chemistry.ConclusionsCDX-585 effectively combines ILT4 and PD-1 blockade into one molecule with favorable biophysical and functional characteristics supporting the initiation of development activities including manufacturing and IND-enabling studies. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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