CLDN18.2 x CD3 bispecifics for targeting gastric and pancreatic cancer

The Target: Claudin 18.2

Claudin 18 isoform 2 (Claudin 18.2 or CLDN18.2) belongs to a family of tight-junction proteins. It is expressed at high levels in many tumor types, including pancreatic and gastric. With the exception of the gastric mucosa, CLDN18.2 is not expressed in healthy adult tissues.

Its restricted expression pattern makes CLDN18.2 an excellent oncology target. However, to be viable as therapeutics, molecules must be selective for CLDN18.2 and minimally cross-reactive with related claudins. These include CLDN18.1, an isoform expressed in healthy lung tissue, which differs by just 8 extracellular amino acids.

A simple model of the Claudin 18.2 protein. Four transmembrane domains span a lipid bilayer, with both the N and C termini inside the cell.
Claudin 18.2 is a complex membrane protein expressed on the surface of gastric, pancreatic, and other cancer cells.

Therapeutic Potential: Specific activity against CLDN18.2-expressing cells

Using our proprietary MPS Antibody Discovery platform, we generated and selected highly specific, humanized CLDN18.2 MAbs. To ensure selectivity for the desired target, clones were deselected against CLDN18.1. Candidate MAbs bind CLDN18.2 with high affinity comparable to or higher than a clinical benchmark (IMAB362, Astellas).

To assess specificity, we screened the lead candidates using our Membrane Proteome Array™. Our panel of CLDN18.2 MAbs is highly specific to the intended target, with no off-target binding to related claudins or to any other proteins in the 6,000-protein array. This binding selectivity minimizes the risk of off-tissue toxicity.

To generate a diverse panel of CLDN18.2 x CD3 bispecific molecules in a variety of formats, we combined CLDN18.2 binding arms with a selection of well-characterized CD3-binding partner arms. We screened the panel for target binding and T cell-directed cytotoxicity. Lead candidates show picomolar potency and high specificity, suggesting they have high therapeutic potential.

Left graph titled “Candidate MAbs show high-affinity binding” plots antibody concentration against cell binding. It compares three Integral Molecular MAbs to a clinical benchmark. Right graph titled “Bispecific target-cell killing is specific to CLDN18.2” plots bispecific antibody concentration against percent specific cytotoxicity. It compares bispecific cytotoxicity against CLDN18.2 and CLDN18.1 cells.

Our CLDN18.2 MAbs show binding affinities comparable to or higher than a clinical benchmark (IMAB362, Astellas) (left ). In a cytotoxicity assay, our CLDN18.2 bispecifics kill CLDN18.2-expressing cells with high specificity and picomolar potency. They do not kill cells expressing closely related CLDN18.1 (right).

The Opportunity: Highly selective, humanized CLDN18.2 x CD3 bispecifics for licensing

Our CLDN18.2 bispecifics are available for licensing, as are the MAbs for non–CAR-T, non-bispecific use. Note that CARTEXELL has licensed our Claudin 18.2 MAbs for development as CAR-T cell therapies.

These are potent, highly specific molecules that show promise for killing gastric and pancreatic cancer cells. The MAbs bind to orthologs in other species, including mice, facilitating animal studies.

For more about the promise of CLDN18.2 as a therapeutic target, see Sahin et al., 2008.

For more assets available to license, visit our Therapeutic Pipeline page

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