CLN-978, a novel half-life extended CD19/CD3/HSA-specific T cell-engaging antibody construct with potent activity against B-cell malignancies with low CD19 expression
Background Despite significant progress in the development of T cell-engaging therapies for various B-cell malignancies, a high medical need remains for the refractory disease setting, often characterized by suboptimal target levels.Methods To address this issue, we have developed a 65-kDa multispec...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-08-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/8/e007398.full |
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| author | Agapitos Patakas Bochong Li Naveen K Mehta Kristan Meetze Patrick A Baeuerle Jennifer S Michaelson Hannah M Findlay Timothy B London |
| author_facet | Agapitos Patakas Bochong Li Naveen K Mehta Kristan Meetze Patrick A Baeuerle Jennifer S Michaelson Hannah M Findlay Timothy B London |
| author_sort | Agapitos Patakas |
| collection | DOAJ |
| description | Background Despite significant progress in the development of T cell-engaging therapies for various B-cell malignancies, a high medical need remains for the refractory disease setting, often characterized by suboptimal target levels.Methods To address this issue, we have developed a 65-kDa multispecific antibody construct, CLN-978, with affinities tuned to optimize the killing of low-CD19 expressing tumor cells. CLN-978 bound to CD19 on B cells with picomolar affinity, and to CD3ε on T cells with nanomolar affinity. A serum albumin binding domain was incorporated to extend serum half-life. In this setting, we biophysically characterize and report the activities of CLN-978 in cell co-culture assays, multiple mouse models and non-human primates.Results Human T cells redirected by CLN-978 could eliminate target cells expressing less than 300 copies of CD19 on their surface. The half-life extension and high affinity for CD19 led to significant antitumor activity in murine lymphoma models at very low doses of CLN-978. In primates, we observed a long serum half-life, deep and sustained depletion of normal B cells, and remarkable tolerability, in particular, reduced cytokine release when CLN-978 was administered subcutaneously.Conclusions CLN-978 warrants further exploration. An ongoing clinical phase 1 trial is investigating safety, pharmacokinetics, pharmacodynamics, and the initial therapeutic potential of subcutaneously administered CLN-978 in patients with non-Hodgkin’s lymphoma. |
| format | Article |
| id | doaj-art-03625d161242477f821871a5ae3d1af8 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2023-08-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-03625d161242477f821871a5ae3d1af82025-02-03T20:15:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-08-0111810.1136/jitc-2023-007398CLN-978, a novel half-life extended CD19/CD3/HSA-specific T cell-engaging antibody construct with potent activity against B-cell malignancies with low CD19 expressionAgapitos Patakas0Bochong Li1Naveen K Mehta2Kristan Meetze3Patrick A Baeuerle4Jennifer S Michaelson5Hannah M Findlay6Timothy B London7Antibody Analytics, Glasgow, UKCullinan Oncology Inc, Cambridge, Massachusetts, USACullinan Oncology Inc, Cambridge, Massachusetts, USACullinan Oncology Inc, Cambridge, Massachusetts, USACullinan Oncology Inc, Cambridge, Massachusetts, USA6Cullinan Oncology, Cambridge, MA, USAAntibody Analytics, Glasgow, UKAntibody Analytics, Glasgow, UKBackground Despite significant progress in the development of T cell-engaging therapies for various B-cell malignancies, a high medical need remains for the refractory disease setting, often characterized by suboptimal target levels.Methods To address this issue, we have developed a 65-kDa multispecific antibody construct, CLN-978, with affinities tuned to optimize the killing of low-CD19 expressing tumor cells. CLN-978 bound to CD19 on B cells with picomolar affinity, and to CD3ε on T cells with nanomolar affinity. A serum albumin binding domain was incorporated to extend serum half-life. In this setting, we biophysically characterize and report the activities of CLN-978 in cell co-culture assays, multiple mouse models and non-human primates.Results Human T cells redirected by CLN-978 could eliminate target cells expressing less than 300 copies of CD19 on their surface. The half-life extension and high affinity for CD19 led to significant antitumor activity in murine lymphoma models at very low doses of CLN-978. In primates, we observed a long serum half-life, deep and sustained depletion of normal B cells, and remarkable tolerability, in particular, reduced cytokine release when CLN-978 was administered subcutaneously.Conclusions CLN-978 warrants further exploration. An ongoing clinical phase 1 trial is investigating safety, pharmacokinetics, pharmacodynamics, and the initial therapeutic potential of subcutaneously administered CLN-978 in patients with non-Hodgkin’s lymphoma.https://jitc.bmj.com/content/11/8/e007398.full |
| spellingShingle | Agapitos Patakas Bochong Li Naveen K Mehta Kristan Meetze Patrick A Baeuerle Jennifer S Michaelson Hannah M Findlay Timothy B London CLN-978, a novel half-life extended CD19/CD3/HSA-specific T cell-engaging antibody construct with potent activity against B-cell malignancies with low CD19 expression Journal for ImmunoTherapy of Cancer |
| title | CLN-978, a novel half-life extended CD19/CD3/HSA-specific T cell-engaging antibody construct with potent activity against B-cell malignancies with low CD19 expression |
| title_full | CLN-978, a novel half-life extended CD19/CD3/HSA-specific T cell-engaging antibody construct with potent activity against B-cell malignancies with low CD19 expression |
| title_fullStr | CLN-978, a novel half-life extended CD19/CD3/HSA-specific T cell-engaging antibody construct with potent activity against B-cell malignancies with low CD19 expression |
| title_full_unstemmed | CLN-978, a novel half-life extended CD19/CD3/HSA-specific T cell-engaging antibody construct with potent activity against B-cell malignancies with low CD19 expression |
| title_short | CLN-978, a novel half-life extended CD19/CD3/HSA-specific T cell-engaging antibody construct with potent activity against B-cell malignancies with low CD19 expression |
| title_sort | cln 978 a novel half life extended cd19 cd3 hsa specific t cell engaging antibody construct with potent activity against b cell malignancies with low cd19 expression |
| url | https://jitc.bmj.com/content/11/8/e007398.full |
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