Targeting CEACAM5-positive solid tumors using NILK-2401, a novel CEACAM5xCD47 κλ bispecific antibody.
CD47
CEACAM5
bispecific antibody
immunotherapy
solid cancer
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2024
2024
Historique:
received:
30
01
2024
accepted:
10
04
2024
medline:
9
5
2024
pubmed:
9
5
2024
entrez:
9
5
2024
Statut:
epublish
Résumé
Blocking the CD47 "don't eat me"-signal on tumor cells with monoclonal antibodies or fusion proteins has shown limited clinical activity in hematologic malignancies and solid tumors thus far. Main side effects are associated with non-tumor targeted binding to CD47 particularly on blood cells. We present here the generation and preclinical development of NILK-2401, a CEACAM5×CD47 bispecific antibody (BsAb) composed of a common heavy chain and two different light chains, one kappa and one lambda, determining specificity (so-called κλ body format). NILK-2401 is a fully human BsAb binding the CEACAM5 N-terminal domain on tumor cells by its lambda light chain arm with an affinity of ≈4 nM and CD47 with its kappa chain arm with an intendedly low affinity of ≈500 nM to enabling tumor-specific blockade of the CD47-SIRPα interaction. For increased activity, NILK-2401 features a functional IgG1 Fc-part. NILK-2401 eliminates CEACAM5-positive tumor cell lines (3/3 colorectal, 2/2 gastric, 2/2 lung) with EC NILK-2401 combines promising preclinical activity with limited potential side effects due to the tumor-targeted blockade of CD47 and low immunogenicity and is planned to enter clinical testing.
Sections du résumé
Background
UNASSIGNED
Blocking the CD47 "don't eat me"-signal on tumor cells with monoclonal antibodies or fusion proteins has shown limited clinical activity in hematologic malignancies and solid tumors thus far. Main side effects are associated with non-tumor targeted binding to CD47 particularly on blood cells.
Methods
UNASSIGNED
We present here the generation and preclinical development of NILK-2401, a CEACAM5×CD47 bispecific antibody (BsAb) composed of a common heavy chain and two different light chains, one kappa and one lambda, determining specificity (so-called κλ body format).
Results
UNASSIGNED
NILK-2401 is a fully human BsAb binding the CEACAM5 N-terminal domain on tumor cells by its lambda light chain arm with an affinity of ≈4 nM and CD47 with its kappa chain arm with an intendedly low affinity of ≈500 nM to enabling tumor-specific blockade of the CD47-SIRPα interaction. For increased activity, NILK-2401 features a functional IgG1 Fc-part. NILK-2401 eliminates CEACAM5-positive tumor cell lines (3/3 colorectal, 2/2 gastric, 2/2 lung) with EC
Conclusion
UNASSIGNED
NILK-2401 combines promising preclinical activity with limited potential side effects due to the tumor-targeted blockade of CD47 and low immunogenicity and is planned to enter clinical testing.
Identifiants
pubmed: 38720892
doi: 10.3389/fimmu.2024.1378813
pmc: PMC11076849
doi:
Substances chimiques
Antibodies, Bispecific
0
CEACAM5 protein, human
0
CD47 Antigen
0
Carcinoembryonic Antigen
0
CD47 protein, human
0
Antineoplastic Agents, Immunological
0
GPI-Linked Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1378813Informations de copyright
Copyright © 2024 Seckinger, Buatois, Moine, Daubeuf, Richard, Chatel, Viandier, Bosson, Rousset, Masternak, Salgado-Pires, Batista, Mougin, Juan-Bégeot, Poitevin and Hose.
Déclaration de conflit d'intérêts
AS and DH declare employment at LamKap Bio Group. VB, VM, BD, FR, LC, AV, NB, ER, KM, CB, CM, FJ-B, and YP declare employment at Light Chain Bioscience - Novimmune SA. SS-P declares consultancy work for Light Chain Bioscience - Novimmune SA and LamKap Bio. The authors declare that this study received funding from LamKap Bio beta. The funder or its employees had the following involvement in the study: study design, data analysis, decision to publish, and preparation of the manuscript. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.