CDX-585, a Bispecific Antibody with Dual Targeting of ILT4 and PD-1 Checkpoint Pathways
Immunoglobulin-like transcript 4 (ILT4) is an immunosuppressive molecule predominantly expressed on myeloid cells. Recent studies combining ILT4 suppression with programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade have shown promising signs of activity in immune checkpoint...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-07-01
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| Series: | Immuno |
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| Online Access: | https://www.mdpi.com/2673-5601/3/3/18 |
| _version_ | 1797579613327589376 |
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| author | Michael B. Murphy Laura Vitale Shukai Xia Zeyu Peng Thomas O’Neill Jay Lillquist Anna Wasiuk Jeff Weidlick Jenifer Widger Laura Mills-Chen Andrea Crocker Colleen Patterson James Boyer April R. Baronas Mingjiu Chen Hugh M. Davis Mark Ma Joel Goldstein Lawrence J. Thomas Diego Alvarado Henry C. Marsh Tibor Keler |
| author_facet | Michael B. Murphy Laura Vitale Shukai Xia Zeyu Peng Thomas O’Neill Jay Lillquist Anna Wasiuk Jeff Weidlick Jenifer Widger Laura Mills-Chen Andrea Crocker Colleen Patterson James Boyer April R. Baronas Mingjiu Chen Hugh M. Davis Mark Ma Joel Goldstein Lawrence J. Thomas Diego Alvarado Henry C. Marsh Tibor Keler |
| author_sort | Michael B. Murphy |
| collection | DOAJ |
| description | Immunoglobulin-like transcript 4 (ILT4) is an immunosuppressive molecule predominantly expressed on myeloid cells. Recent studies combining ILT4 suppression with programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade have shown promising signs of activity in immune checkpoint inhibitor refractory patients. We theorized that coupling ILT4 and PD-1/PD-L1 blockade in a bispecific antibody (bsAb) may provide greater immune activating properties than combining the individual mAbs due to enhanced bridging of APCs to T cells. To test this approach, we developed CDX-585, a tetravalent ILT4xPD-1 IgG1-scFv bsAb from novel PD-1 and ILT-4 mAbs. CDX-585 is a potent antagonist of both PD-1 and ILT4. CDX-585 promotes M1 macrophage polarization and enhances pro-inflammatory cytokine secretion in response to lipopolysaccharide or CD40 agonist mAb treatment. In mixed lymphocyte reaction (MLR) assays, CDX-585 is more potent than the combination of parental antibodies. In a humanized NCG mouse SK-MEL-5 tumor model, CDX-585 exhibits greater antitumor activity than the combination of parental mAbs. A pilot study of CDX-585 in cynomolgus macaques confirmed a mAb-like pharmacokinetic profile without noted toxicities. These studies demonstrate that CDX-585 effectively combines ILT4 and the PD-1 blockade into one molecule that is more potent than the combination of the parental antibodies, providing the rationale to advance this bsAb into clinical studies. |
| first_indexed | 2024-03-10T22:38:40Z |
| format | Article |
| id | doaj.art-e24496d39a404eb1a00b6ba38c57bbb8 |
| institution | Directory Open Access Journal |
| issn | 2673-5601 |
| language | English |
| last_indexed | 2024-03-10T22:38:40Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Immuno |
| spelling | doaj.art-e24496d39a404eb1a00b6ba38c57bbb82023-11-19T11:13:21ZengMDPI AGImmuno2673-56012023-07-013327328810.3390/immuno3030018CDX-585, a Bispecific Antibody with Dual Targeting of ILT4 and PD-1 Checkpoint PathwaysMichael B. Murphy0Laura Vitale1Shukai Xia2Zeyu Peng3Thomas O’Neill4Jay Lillquist5Anna Wasiuk6Jeff Weidlick7Jenifer Widger8Laura Mills-Chen9Andrea Crocker10Colleen Patterson11James Boyer12April R. Baronas13Mingjiu Chen14Hugh M. Davis15Mark Ma16Joel Goldstein17Lawrence J. Thomas18Diego Alvarado19Henry C. Marsh20Tibor Keler21Celldex Therapeutics, Inc., Hampton, NJ 08827, USACelldex Therapeutics, Inc., Hampton, NJ 08827, USABiosion, Inc., Nanjing 210061, ChinaBiosion, Inc., Nanjing 210061, ChinaCelldex Therapeutics, Inc., Hampton, NJ 08827, USACelldex Therapeutics, Inc., Hampton, NJ 08827, USACelldex Therapeutics, Inc., Hampton, NJ 08827, USACelldex Therapeutics, Inc., Hampton, NJ 08827, USACelldex Therapeutics, Inc., Hampton, NJ 08827, USACelldex Therapeutics, Inc., Hampton, NJ 08827, USACelldex Therapeutics, Inc., Hampton, NJ 08827, USACelldex Therapeutics, Inc., Hampton, NJ 08827, USACelldex Therapeutics, Inc., Hampton, NJ 08827, USACelldex Therapeutics, Inc., Hampton, NJ 08827, USABiosion, Inc., Nanjing 210061, ChinaBiosion, Inc., Nanjing 210061, ChinaBiosion, Inc., Nanjing 210061, ChinaCelldex Therapeutics, Inc., Hampton, NJ 08827, USACelldex Therapeutics, Inc., Hampton, NJ 08827, USACelldex Therapeutics, Inc., Hampton, NJ 08827, USACelldex Therapeutics, Inc., Hampton, NJ 08827, USACelldex Therapeutics, Inc., Hampton, NJ 08827, USAImmunoglobulin-like transcript 4 (ILT4) is an immunosuppressive molecule predominantly expressed on myeloid cells. Recent studies combining ILT4 suppression with programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade have shown promising signs of activity in immune checkpoint inhibitor refractory patients. We theorized that coupling ILT4 and PD-1/PD-L1 blockade in a bispecific antibody (bsAb) may provide greater immune activating properties than combining the individual mAbs due to enhanced bridging of APCs to T cells. To test this approach, we developed CDX-585, a tetravalent ILT4xPD-1 IgG1-scFv bsAb from novel PD-1 and ILT-4 mAbs. CDX-585 is a potent antagonist of both PD-1 and ILT4. CDX-585 promotes M1 macrophage polarization and enhances pro-inflammatory cytokine secretion in response to lipopolysaccharide or CD40 agonist mAb treatment. In mixed lymphocyte reaction (MLR) assays, CDX-585 is more potent than the combination of parental antibodies. In a humanized NCG mouse SK-MEL-5 tumor model, CDX-585 exhibits greater antitumor activity than the combination of parental mAbs. A pilot study of CDX-585 in cynomolgus macaques confirmed a mAb-like pharmacokinetic profile without noted toxicities. These studies demonstrate that CDX-585 effectively combines ILT4 and the PD-1 blockade into one molecule that is more potent than the combination of the parental antibodies, providing the rationale to advance this bsAb into clinical studies.https://www.mdpi.com/2673-5601/3/3/18macrophagesdendritic cellsT cellsimmunotherapycancerbispecific antibodies |
| spellingShingle | Michael B. Murphy Laura Vitale Shukai Xia Zeyu Peng Thomas O’Neill Jay Lillquist Anna Wasiuk Jeff Weidlick Jenifer Widger Laura Mills-Chen Andrea Crocker Colleen Patterson James Boyer April R. Baronas Mingjiu Chen Hugh M. Davis Mark Ma Joel Goldstein Lawrence J. Thomas Diego Alvarado Henry C. Marsh Tibor Keler CDX-585, a Bispecific Antibody with Dual Targeting of ILT4 and PD-1 Checkpoint Pathways Immuno macrophages dendritic cells T cells immunotherapy cancer bispecific antibodies |
| title | CDX-585, a Bispecific Antibody with Dual Targeting of ILT4 and PD-1 Checkpoint Pathways |
| title_full | CDX-585, a Bispecific Antibody with Dual Targeting of ILT4 and PD-1 Checkpoint Pathways |
| title_fullStr | CDX-585, a Bispecific Antibody with Dual Targeting of ILT4 and PD-1 Checkpoint Pathways |
| title_full_unstemmed | CDX-585, a Bispecific Antibody with Dual Targeting of ILT4 and PD-1 Checkpoint Pathways |
| title_short | CDX-585, a Bispecific Antibody with Dual Targeting of ILT4 and PD-1 Checkpoint Pathways |
| title_sort | cdx 585 a bispecific antibody with dual targeting of ilt4 and pd 1 checkpoint pathways |
| topic | macrophages dendritic cells T cells immunotherapy cancer bispecific antibodies |
| url | https://www.mdpi.com/2673-5601/3/3/18 |
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