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Emiltatug ledadotin (Emi-Le)

Adenoid cystic carcinoma with solid histology or high-grade transformation

Also known as XMT-1660
Manufacturer
Servier
Regulatory submission
Not announced
Launch
Not announced
Last updated
125 sources

Product information and disease descriptionProduct descriptionProduct informationPharmacology

Mechanism of action

4 evidence topics · 3 sources

Target: B7-H4

“B7-H4 (VTCN1) is a member of the B7 immune checkpoint family with a distinct expression pattern from classical checkpoint pathways. It acts as an immunosuppressant that regulates the innate and adaptive immune systems and is associated with exclusion of T cells from the tumor microenvironment.” (opens the source at this quote in a new tab)

“Its expression in normal human tissue is generally reported to be limited, but it is highly expressed on multiple tumor types with high unmet need, including breast, endometrial and ovarian cancers and ACC-1.” (opens the source at this quote in a new tab)

Antibody: human IgG1 without B7-H4 function-blocking activity

“The selected antibody (XMT-1604) is a human IgG1 kappa monoclonal antibody that specifically binds to human B7-H4 with sub nanomolar affinity and exhibits comparable binding profiles to recombinant B7-H4 from human, cynomolgus monkey, mouse, and rat (Supplementary Table S3).” (opens the source at this quote in a new tab)

“These data indicate that the B7-H4 antibody does not exhibit function-blocking activity.” (opens the source at this quote in a new tab)

Dolasynthen platform and selection of drug-to-antibody ratio 6

“To allow for ADC optimization for a given target antigen, we developed Dolasynthen (DS), a novel ADC platform based on the payload auristatin hydroxypropylamide, that enables precise DAR-ranging and site-specific conjugation.” (opens the source at this quote in a new tab)

“In the case of B7-H4, the site-specific DS DAR 6 ADC (XMT-1660) exhibited superior in vivo antitumor activity and noninferior in vitro, pharmacokinetics, and toxicology profiles relative to the DS DAR 2 and DF DAR 12 ADCs.” (opens the source at this quote in a new tab)

Payload: auristatin F-HPA and controlled bystander effect

“A distinguishing feature of the payload in the DF platform, auristatin F hydroxypropylamide (AF-HPA), is its controlled bystander effect. In general, bystander effect is the ability of an ADC to indirectly cause the death of antigen-negative cells; for instance, by the diffusion of payload delivered to antigen-positive cells into neighboring antigen-negative cells. In the case of DF, the ability of AF-HPA to diffuse into neighboring tumor cells is balanced by the intracellular conversion of AF-HPA to AF, a molecule that is highly active intracellularly and gets trapped in tumor cells because it is less membrane permeable and not a PgP substrate.” (opens the source at this quote in a new tab)

“Dolasynthen utilizes the same proprietary auristatin anti-tubulin payload that was utilized in Dolaflexin.” (opens the source at this quote in a new tab)

“Moreover, because our auristatin payload targets tubulin, it is not dependent on the expression or mutational status of topoisomerase-1 or topoisomerase-2 enzymes, which we believe may allow it to avoid topo-1-related resistance mechanisms.” (opens the source at this quote in a new tab)