Fig. 4: Evaluation of ADCs with phosphorus-based self-immolative linkers and aliphatic alcohols, exemplified with DXd. | Nature Communications

Fig. 4: Evaluation of ADCs with phosphorus-based self-immolative linkers and aliphatic alcohols, exemplified with DXd.

From: Expanding the payload scope in antibody-drug conjugates by delivery of hydroxy-containing drugs through self-immolative phosphoramidates

Fig. 4: Evaluation of ADCs with phosphorus-based self-immolative linkers and aliphatic alcohols, exemplified with DXd.The alternative text for this image may have been generated using AI.

a DAR8 ADCs from trastuzumab (tras/anti-HER2) using DXd and protease-cleavable release handles (highlighted with purple background) that initiate release via 5-membered cyclization. b Linker-payload structures 1-DXd (highlighted with turquoise background) and 3-DXd (highlighted with orange background) after cysteine conjugation. c Linker-payload structures 14−17-DXd after cysteine conjugation. Alanine-alanine tert-butyl ester release handle highlighted with green Background, di-alanine release handle highlighted with purple background, beta-alanine-alanine release handle highlighted with yellow background and gamma-aminobutyric acid-alanine release handle highlighted with red background. d Evaluation of trastuzumab-1- (turquoise) and -3-DXd (orange) in comparison to isotype controls. Comparison of esterase cleavable trastuzumab-3-DXd (orange) to protease cleavable 14-DXd (green) and 15-DXd (purple) in comparison to isotype controls (middle). Comparison of trastuzumab-15-DXd (purple), 16-DXd (brown) and 17-DXd (pink) that can form a 5-, 6-, or 7-membered ring after protease cleavage in comparison to isotype controls (right). Anti-proliferative dose response curves for targeting ADCs (solid) and isotype-ADCs (dashed) on SKBR-3 cells (HER2 + ). Mean, n = 2. e Rat serum stability: DAR measured by mass spectrometry of tras-15-DXd (purple) or TD (gray) after incubation for up to 5 days in rat serum at 37 °C. Mean, n = 2. f In vivo efficacy evaluation of tras-15-DXd (purple open upward-pointing triangle), iso-15-DXd (purple filled downward-pointing triangle), TD (gray open circle) or vehicle (black filled diamond) (left). Female CB17 SCID mice have been implanted with cell-culture-derived xenograft model based on N87 cells in matrigel. Treatment started once when tumor volumes reached 0.1–0.15 cm3. Mice were treated once at day 0 with 1 mg/kg of the ADCs. Each group consisted of n = 5 females each. Shown is the Mean ± SEM of the 5 animals. TD trastuzumab deruxtecan, CR complete responses of total mice treated. Pharmacokinetic analysis of CB17-SCID mice treated with 1 mg/kg of either tras-15-DXd (purple) or TD (gray) (right). Samples were drawn after several timepoints throughout the 3-week study period. The serum samples were analyzed by ELISA for total mAb with anti-HER2 antibodies (straight line) and intact ADC with anti-payload antibodies (dotted line).

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