| Autor: |
Anja Seckinger, Sara Majocchi, Valéry Moine, Lise Nouveau, Hoang Ngoc, Bruno Daubeuf, Ulla Ravn, Nicolas Pleche, Sebastien Calloud, Lucile Broyer, Laura Cons, Adeline Lesnier, Laurence Chatel, Anne Papaioannou, Susana Salgado-Pires, Sebastian Krämer, Ines Gockel, Florian Lordick, Krzysztof Masternak, Yves Poitevin, Giovanni Magistrelli, Pauline Malinge, Limin Shang, Sonja Kallendrusch, Klaus Strein, Dirk Hose |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Journal of Hematology & Oncology, Vol 16, Iss 1, Pp 1-23 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
1756-8722 |
| DOI: |
10.1186/s13045-023-01516-3 |
| Popis: |
Abstract Background T-cell retargeting to eliminate CEACAM5-expressing cancer cells via CEACAM5xCD3 bispecific antibodies (BsAbs) showed limited clinical activity so far, mostly due to insufficient T-cell activation, dose-limiting toxicities, and formation of anti-drug antibodies (ADA). Methods We present here the generation and preclinical development of NILK-2301, a 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 NILK-2301 binds CD3ɛ on T-cells with its lambda light chain arm with an affinity of ≈100 nM, and the CEACAM5 A2 domain on tumor cells by its kappa light chain arm with an affinity of ≈5 nM. FcγR-binding is abrogated by the “LALAPA” mutation (Leu234Ala, Leu235Ala, Pro329Ala). NILK-2301 induced T-cell activation, proliferation, cytokine release, and T-cell dependent cellular cytotoxicity of CEACAM5-positive tumor cell lines (5/5 colorectal, 2/2 gastric, 2/2 lung), e.g., SK-CO-1 (E max = 89%), MKN-45 (E max = 84%), and H2122 (E max = 97%), with EC50 ranging from 0.02 to 0.14 nM. NILK-2301 binds neither to CEACAM5-negative or primary colon epithelial cells nor to other CEACAM family members. NILK-2301 alone or in combination with checkpoint inhibition showed activity in organotypic tumor tissue slices and colorectal cancer organoid models. In vivo, NILK-2301 at 10 mg/kg significantly delayed tumor progression in colon- and a pancreatic adenocarcinoma model. Single-dose pharmacokinetics (PK) and tolerability in cynomolgus monkeys at 0.5 or 10 mg/kg intravenously or 20 mg subcutaneously showed dose-proportional PK, bioavailability ≈100%, and a projected half-life in humans of 13.1 days. NILK-2301 was well-tolerated. Data were confirmed in human FcRn TG32 mice. Conclusions In summary, NILK-2301 combines promising preclinical activity and safety with lower probability of ADA-generation due to its format compared to other molecules and is scheduled to enter clinical testing at the end of 2023. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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