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798 CDX-585, A bispecific antibody with dual targeting of ILT4 and PD-1 checkpoint pathways
  1. Laura Vitale1,
  2. Michael Murphy2,
  3. Collin Xia3,
  4. Zeyu Peng3,
  5. Thomas O'Neill2,
  6. Ed Natoli2,
  7. Jay Lillquist2,
  8. Linda Crew2,
  9. Anna Wasiuk2,
  10. Jeff Weidlick2,
  11. Jenifer Widger2,
  12. Laura Mills-Chen2,
  13. Andrea Crocker2,
  14. Colleen Patterson2,
  15. James Boyer2,
  16. April Baronas2,
  17. Russell Hammond2,
  18. Hugh Davis3,
  19. Mark Ma3,
  20. Joel Goldstein2,
  21. Lawrence Thomas2,
  22. Diego Alvarado2,
  23. Henry Marsh2 and
  24. Tibor Keler2
  1. 1Celldex Therpeutics, Hampton, NJ, United States
  2. 2Celldex Therapeutics, New Haven, CT, United States
  3. 3Biosion, Inc., Nanjing, China


Background Activation 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.

Methods We 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.

Results CDX-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.

Conclusions CDX-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.

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