Antibody-drug conjugates (ADCs) using DNA Topoisomerase I inhibitor DXd/SN-38 have transformed cancer treatment, yet more effective ADCs are needed for overcoming resistance. We have designed an ADC class using a novel self-immolative T moiety for traceless conjugation and release of exatecan, a more potent Topoisomerase I inhibitor with less sensitivity to multidrug (MDR) resistance. Characterized by enhanced therapeutic indices, higher stability and improved intra-tumoral pharmacodynamic response, antibody-T moiety-exatecan conjugates targeting HER2, HER3, TROP2 overcome intrinsic or treatment-resistance of equivalent DXd/SN-38 ADCs in low-target expression, large-size and MDR+ tumors. T moiety-exatecan ADCs display durable antitumor activity in PDX and organoid models representative of unmet clinical needs including EGFR-del19/T790M/C797S triple mutation lung cancer and BRAF/KRAS–TP53 double-mutant colon cancer, and show synergy with PARP/ATR inhibitor and anti-PD-1 treatment. High tolerability of T moiety-exatecan ADC class in non-human primate supports its potential to expand responding patient population and tumor types beyond current ADCs.
<p>Supplementary Figure S1 shows Exatecan cytotoxicity and sensitivity to multidrug resistant genes. Supplementary Figure S2 shows Exatecan and DXd/SN-38 sensitivity to multidrug resistant genes. Supplementary Figure S3 shows Exatecan toxicity in rat. Supplementary Figure S4 shows the design and optimization of T moiety. Supplementary Figure S5 shows physicochemical and functional equivalence of Tras-GGFG-DXd and DS-8201a. Supplementary Figure S6 show physicochemical profile of antibody-exatecan conjugates enabled by T moiety. Supplementary Figure S7 shows additional T moiety-exatecan and belotecan conjugates. Supplementary Figure S8 shows in vitro and in vivo stability of MTX-1000. Supplementary Figure S9 shows cellular dynamics and mechanism of MTX-1000. Supplementary Figure S10 shows colon cancer organoid response to ADCs. Supplementary Figure S11 shows bystander killing effect of MTX-1000, T-DM1 and Tras-GGFG-DXd in coculture conditions in vitro. Supplementary Figure S12 shows hematology and serum chemistry of MTX-1000 in monkey. Supplementary Figure S13 shows T moiety-exatecan ADCs show potent antitumor efficacy and improved therapeutic index. Supplementary Figure S14 shows T moiety-exatecan ADCs show higher antitumor potency in PDX models and better intratumor pharmacodynamic response. Supplementary Figure S15 shows T moiety-exatecan ADCs overcome treatment-resistance due to improved therapeutic index and intratumor pharmacodynamic response. Supplementary Figure S16 shows overcoming MDR resistance by T moiety exatecan ADCs or a combination of MDR inhibitor with DXd/SN-38 ADCs. Supplementary Figure S17 shows Exatecan/MTX-1000 and PARP/ATR inhibitor synergize in colon cancer cells. Supplementary Figure S18 shows a patient-derived xenograft (PDX) model with EGFR triple mutation. Supplementary Figure S19 shows MTX-1000 induces immunological cell death and enhances antitumor immunity of anti-PD-1.</p>
<div>Abstract<p>Antibody–drug conjugates (ADC) using DNA topoisomerase I inhibitor DXd/SN-38 have transformed cancer treatment, yet more effective ADCs are needed for overcoming resistance. We have designed an ADC class using a novel self-immolative T moiety for traceless conjugation and release of exatecan, a more potent topoisomerase I inhibitor with less sensitivity to multidrug resistance (MDR). Characterized by enhanced therapeutic indices, higher stability, and improved intratumoral pharmacodynamic response, antibody–T moiety–exatecan conjugates targeting HER2, HER3, and TROP2 overcome the intrinsic or treatment resistance of equivalent DXd/SN-38 ADCs in low-target-expression, large, and MDR<sup>+</sup> tumors. T moiety–exatecan ADCs display durable antitumor activity in patient-derived xenograft and organoid models representative of unmet clinical needs, including <i>EGFR</i> ex19del/T790M/C797S triple-mutation lung cancer and <i>BRAF/KRAS–TP53</i> double-mutant colon cancer, and show synergy with PARP/ATR inhibitor and anti–PD-1 treatment. High tolerability of the T moiety–exatecan ADC class in nonhuman primates supports its potential to expand the responding patient population and tumor types beyond current ADCs.</p>Significance:<p>ADCs combining a novel self-immolative moiety and topoisomerase I inhibitor exatecan as payload show deep and durable response in low-target-expressing and MDR<sup>+</sup> tumors resistant to DXd/SN-38 ADCs without increasing toxicity. This new class of ADCs has the potential to benefit an additional patient population beyond current options.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-23-0091" target="_blank">See related commentary by Gupta et al., p. 817.</a></i></p><p><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-13-4-ITI" target="_blank">This article is highlighted in the In This Issue feature, p. 799</a></p></div>
<p>Supplementary Figure S1 shows Exatecan cytotoxicity and sensitivity to multidrug resistant genes. Supplementary Figure S2 shows Exatecan and DXd/SN-38 sensitivity to multidrug resistant genes. Supplementary Figure S3 shows Exatecan toxicity in rat. Supplementary Figure S4 shows the design and optimization of T moiety. Supplementary Figure S5 shows physicochemical and functional equivalence of Tras-GGFG-DXd and DS-8201a. Supplementary Figure S6 show physicochemical profile of antibody-exatecan conjugates enabled by T moiety. Supplementary Figure S7 shows additional T moiety-exatecan and belotecan conjugates. Supplementary Figure S8 shows in vitro and in vivo stability of MTX-1000. Supplementary Figure S9 shows cellular dynamics and mechanism of MTX-1000. Supplementary Figure S10 shows colon cancer organoid response to ADCs. Supplementary Figure S11 shows bystander killing effect of MTX-1000, T-DM1 and Tras-GGFG-DXd in coculture conditions in vitro. Supplementary Figure S12 shows hematology and serum chemistry of MTX-1000 in monkey. Supplementary Figure S13 shows T moiety-exatecan ADCs show potent antitumor efficacy and improved therapeutic index. Supplementary Figure S14 shows T moiety-exatecan ADCs show higher antitumor potency in PDX models and better intratumor pharmacodynamic response. Supplementary Figure S15 shows T moiety-exatecan ADCs overcome treatment-resistance due to improved therapeutic index and intratumor pharmacodynamic response. Supplementary Figure S16 shows overcoming MDR resistance by T moiety exatecan ADCs or a combination of MDR inhibitor with DXd/SN-38 ADCs. Supplementary Figure S17 shows Exatecan/MTX-1000 and PARP/ATR inhibitor synergize in colon cancer cells. Supplementary Figure S18 shows a patient-derived xenograft (PDX) model with EGFR triple mutation. Supplementary Figure S19 shows MTX-1000 induces immunological cell death and enhances antitumor immunity of anti-PD-1.</p>
<p>Supplementary note shows the analytical characterization of the ADCs, and synthesis of drug-linkers</p>
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