(1) Toader D (2) Fessler SP (3) Collins SD (4) Conlon PR (5) Bollu R (6) Catcott KC (7) Chin CN (8) Dirksen A (9) Du B (10) Duvall JR (11) Higgins S (12) Kozytska MV (13) Bellovoda K (14) Faircloth C (15) Lee D (16) Li F (17) Qin L (18) Routhier C (19) Shaw P (20) Stevenson CA (21) Wang J (22) Wongthida P (23) Ter-Ovanesyan E (24) Ditty E (25) Bradley SP (26) Xu L (27) Yin M (28) Yurkovetskiy AV (29) Mosher R (30) Damelin M (31) Lowinger TB

Molecular cancer therapeutics

Antibody-drug conjugates (ADCs) achieve targeted drug delivery to a tumor and have demonstrated clinical success in many tumor types. The activity and safety profile of an ADC depends on its construction: antibody, payload, linker, and conjugation method, as well as the number of payload drugs per antibody (drug-to-antibody ratio, DAR). To allow for ADC optimization for a given target antigen, we developed Dolasynthen, a novel ADC platform based on the payload auristatin hydroxypropylamide (AF-HPA), that enables precise DAR-ranging and site-specific conjugation. We used the new platform to optimize an ADC that targets B7-H4 (VTCN1), an immune-suppressive protein that is overexpressed in breast, ovarian, and endometrial cancers. XMT-1660 is a site-specific Dolasynthen DAR 6 ADC that induced complete tumor regressions in xenograft models of breast and ovarian cancer as well as in a syngeneic breast cancer model that is refractory to PD-1 immune checkpoint inhibition. In a panel of 28 breast cancer patient-derived xenografts (PDX), XMT-1660 demonstrated activity that correlated with B7-H4 expression. XMT-1660 has recently entered clinical development in a Phase 1 study (NCT05377996) in cancer patients.

Author Info: (1) Mersana Therapeutics (United States), Cambridge, MA, United States. (2) Matchpoint Therapeutics, Cambridge, MA, United States. (3) Mersana Therapeutics, Cambridge, MA, United S

Author Info: (1) Mersana Therapeutics (United States), Cambridge, MA, United States. (2) Matchpoint Therapeutics, Cambridge, MA, United States. (3) Mersana Therapeutics, Cambridge, MA, United States. (4) Mersana Therapeutics, Inc., Cambridge, MA, United States. (5) Mersana Therapeutics, Cambridge, MA, United States. (6) Mersana Therapeutics (United States), Cambridge, MA, United States. (7) Mersana Therapeutics, Cambridge, MA, United States. (8) Mersana Therapeutics, Cambridge, MA, United States. (9) Mersana Therapeutics, Cambridge, MA, United States. (10) Mersana Therapeutics (United States), Cambridge, United States. (11) Mersana Therapeutics, Cambridge, MA, United States. (12) Mersana Therapeutics, Cambridge, MA, United States. (13) Mersana Therapeutics (United States), Cambridge, MA, United States. (14) Mersana Therapeutics (United States), Cambridge, MA, United States. (15) Mersana Therapeutics (United States), Cambridge, MA, United States. (16) The Ohio State University, Cambridge, MA, United States. (17) Mersana Therapeutics, Cambridge, MA, United States. (18) Mersana Therapeutics, Cambridge, MA, United States. (19) Mersana Therapeutics, Cambridge, ma, United States. (20) Mersana Therapeutics, Inc., Cambridge, MA, United States. (21) Mersana Therapeutics, Cambridge, MA, United States. (22) Mayo Foundation, Rochester, MN, United States. (23) Mersana Therapeutics, Inc., Cambridge, MA, United States. (24) Mersana Therapeutics, Cambridge, MA, United States. (25) Apellis Pharmaceuticals (United States), Waltham, MA, United States. (26) Mersana Therapeutics, Cambridge, United States. (27) Mersana Therapeutics, Cambridge, MA, United States. (28) Valley Cross Consulting, Inc, North Grafton, MA, United States. (29) MERSANA THERAPEUTICS, Cambridge, MA, United States. (30) Mersana Therapeutics (United States), Cambridge, MA, United States. (31) Mersana Therapeutics, Inc., Cambridge, MA, United States.

Citation: Mol Cancer Ther 2023 Jun 9 Epub06/09/2023

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/37294948

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