| Reference | ||
|---|---|---|
| Reference Type | Literature | IEDB_Reference:1045710 |
| Title | Biparatopic binding of ISB 1442 to CD38 in trans enables increased cell antibody density and increased avidity. | |
| Authors | Jeremy Loyau; Thierry Monney; Marco Montefiori; Fedir Bokhovchuk; Jeremy Streuli; Matthew Blackburn; Arnaud Goepfert; Lydia N Caro; Samitabh Chakraborti; Stefania De Angelis; Camille Grandclément; Stanislas Blein; M Lamine Mbow; Ankita Srivastava; Mario Perro; Stefano Sammicheli; Eugene A Zhukovsky; Michael Dyson; Cyrille Dreyfus | |
| Affiliations | Ichnos Glenmark Innovation, New York, NY, USA. | |
| Journal | MAbs | |
| Year | 2025 | |
| Abstract | ISB 1442 is a bispecific biparatopic antibody in clinical development to treat hematological malignancies. It consists of two adjacent anti-CD38 arms targeting non-overlapping epitopes that preferentially drive binding to tumor cells and a low-affinity anti-CD47 arm to enable avidity-induced blocking of proximal CD47 receptors. We previously reported the pharmacology of ISB 1442, designed to reestablish synthetic immunity in CD38+ hematological malignancies. Here, we describe the discovery, optimization and characterization of the ISB 1442 antigen binding fragment (Fab) arms, their assembly to 2 + 1 format, and present the high-resolution co-crystal structures of the two anti-CD38 Fabs, in complex with CD38. This, with biophysical and functional assays, elucidated the underlying mechanism of action of ISB 1442. In solution phase, ISB 1442 forms a 2:2 complex with CD38 as determined by size-exclusion chromatography with multi-angle light scattering and electron microscopy. The predicted antibody-antigen stoichiometries at different CD38 surface densities were experimentally validated by surface plasmon resonance and cell binding assays. The specific design and structural features of ISB 1442 enable: 1) enhanced trans binding to adjacent CD38 molecules to increase Fc density at the cancer cell surface; 2) prevention of avid cis binding to monomeric CD38 to minimize blockade by soluble shed CD38; and 3) greater binding avidity, with a slower off-rate at high CD38 density, for increased specificity. The superior CD38 targeting of ISB 1442, at both high and low receptor densities, by its biparatopic design, will enhance proximal CD47 blockade and thus counteract a major tumor escape mechanism in multiple myeloma patients. | |
| Curation Last Updated | 2025-03-25 20:01:03 | |
| Epitope | ||
|---|---|---|
| Epitope ID | 2275414 | IEDB_epitope:2275414 |
| Chemical Type | Discontinuous peptide | |
| Source Name | ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 | |
| Source Organism | Homo sapiens (human) | |
| Discontinuous Residues | D202, H228, Q231, P232, E233, K234, V235, Q236, S267, K268, R269, N270 | |
| Epitope Reference Details | ||
|---|---|---|
| Epitope Structure Defines | Exact Epitope | |
| Epitope Name | Epitope of Fab B6-D9 on hCD38 | |
| Reference Region | D202, H228, Q231, P232, E233, K234, V235, Q236, S267, K268, R269, N270 | |
| Comments | The epitope residues were calculated from [PDB: 9GOX] as the antigen residues at 4Å atomic distance from the antibody. | |
| Location of Data in Reference | PDB 9GOX | |
| Immunization | ||
|---|---|---|
| Host Organism | Homo sapiens (human) | |
| 1st In Vivo Process | ||
|---|---|---|
| In Vivo Process Type | No immunization | |
| Immunization Comments | ||
|---|---|---|
| Immunization Comments | A synthetic common light chain (cLC) antibody phage display library using a fixed Vκ3-15/Jκ light chain was generated and paired with four germline variable heavy chain frameworks. Optimized natural position-specific diversity was introduced in HCDRs and diversified scFv were transformed into E. coli. Phage display libraries were panned against hCD38 and reformatted to Fabs for characterization. Selected Fabs were subjected to in vitro affinity maturation and randomized libraries panned under high stringency conditions. Sequence-unique clones with a slower dissociation rate (off-rate) than their respective parental clones were reformatted and expressed as Fabs. | |
| B Cell Assay | ||
|---|---|---|
| Qualitative Measurement | Positive | |
| Method/Technique | surface plasmon resonance (SPR) | |
| Measurement of | dissociation constant KD | |
| Assay Type Units | nM | |
| Measurement Details | ||
|---|---|---|
| Measurement Inequality | = | |
| Quantitative measurement | 1.4 | |
| Assayed Antibody | ||
|---|---|---|
| Assayed Antibody Source Material | Antibody construct | |
| Assayed Antibody Immunoglobulin Domain | Fab | |
| Assayed Antibody Purification Status | Display Library (monoclonal) | |
| Assayed Antibody Name | B6-D9 | |
| Assayed Antibody Heavy Chain Type | IgG1 | |
| Assayed Antibody Light Chain Type | Kappa | |
| Assayed Antibody Object | ||
|---|---|---|
| Chemical Type | Multi-Chain protein | |
| Chain 1 Accession Name | Chain H, Fab B6-D9 heavy chain | |
| Source Organism | Homo sapiens (human) | |
| Molecule Name | B6-D9 | |
| Chain 2 Name | Chain L, Fab B6-D9 light chain | |
| Source Organism | Homo sapiens (human) | |
| Antigen | ||
|---|---|---|
| Epitope Relation | Structurally Related | |
| Chemical Type | Protein | |
| Molecule Name | ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 | |
| Organism | Macaca fascicularis (crab eating macaque) | |
| Assay Reference Details | ||
|---|---|---|
| Assay Comments by IEDB Curator | Binding affinity of Fab B6-D9 for cynomolgus CD38 was determined by SPR. | |
| Location of Assay Data in Reference | Table 1 | |