REVOLUTIONIZING TARGETED CANCER THERAPY WITH NEXT-GENERATION ANTIBODY-DRUG CONJUGATES (ADCs)

OVERCOMING TOXICITY AND RESISTANCE IN TRADITIONAL ADCs

Antibody-drug conjugates have long offered immense promise as targeted anti-cancer therapies. However traditional ADC technologies still face major shortcomings in dose-limiting systemic toxicity, therapeutic resistance, and suboptimal stability that together undermine efficacy. Our multi-pronged ADC platform is overcoming these intrinsic flaws by pioneering next-generation linker and payload chemistries.

High throughput FRET-based screen to identify novel cleavable linkers

PIONEERING NEW LINKERS: PRECISION ACTIVATION WITH LEGUMAIN SYSTEM

At the core of our ADC technology lies an innovative legumain-activated linker system enabling localized payload release specifically within the tumor microenvironment. Legumain is a cysteine protease upregulated across cancers compared to healthy tissue. Our custom peptide linker incorporates legumain-cleavable sequences that remain stable in circulation but facilitate rapid activation upon exposure to lysosomal legumain following ADC internalization into tumor cells. This controlled, cancer cell-specific activation prevents systemic drug release, increasing localized cytotoxicity at malignant sites while avoiding healthy tissue

ADVANCING NEXT-GENERATION TOP1i WARHEADS

We are optimizing cutting-edge topoisomerase I inhibitor (TOP1i) payloads that drive cancer cell death by overloading native DNA repair processes and generating irreparable DNA double strand breaks. Specifically, we have developed exatecan derivatives coupled to legumain cleavable linkers to release these potent cytotoxins in the lysosomes of tumor cells. While exceptionally cytotoxic, payload resistance mechanisms and dose-limiting toxicity have challenged their clinical success. By targeted tumor delivery, our legumain linker enables circumventing these limitations to finally harness the power of this unique payload class. Moreover, by leveraging vast in-house linker and payload libraries coupled with innovations in synthetic chemistry and bioconjugation techniques, we are continually pioneering new generations of tumor-selective linker-payload systems to enhance targeted delivery and therapeutic action of the ultra-potent cytotoxins

FDA-APPROVED ENHERTU® (TRASTUZUMAB DERUXTECAN)

Interstitial lung disease (ILD)/pneumonitis is an important risk for patients treated with T-DXd and must be closely monitored and managed according to recommended guidelines

DRAWBACKS OF CLEAVABLE GGFG LINKERS

• The glycyl-glycyl-phenylalanyl-glycine (GGFG) peptide linker used in ENHERTU®  is subject to some degree of premature cathepsin cleavage like val-cit linkers
• Cathepsin heterogeneity and overexpression: Cathepsins like Cathepsin B/L are quite heterogeneous and overexpressed in some tissue types beyond tumors. This could lead to off-target cleavage of the GGFG linker, especially in macrophages, releasing the cytotoxic payload prematurely before reaching the tumor
• Albumin binding variability: While the GGFG linker binds albumin in theory to prevent premature release, the strength and duration of albumin binding may vary depending on environmental conditions in circulation and the tumor microenvironment

DRAWBACKS OF CLEAVABLE VAL-CIT LINKERS

• Ubiquitous expression of cathepsin B/L/S proteases that cleave linker leads to premature release, systemic exposure, and toxicity
• Non-selective activation in blood by circulating proteases degrading linker over time in circulation even before reaching tumor
• Variable linker stability depending on tumor microenvironment protease expression
• Risk of drug resistance if target antigen is downregulated, exposing cytotoxic payload to systemic circulation
• Myelosuppression, which is most likely caused by premature linker cleavage and payload release

REALIZING THE FULL POTENTIAL OF ADCS

By enhancing stability prior to activation, precision tumor targeting, and leveraging next-generation payloads, our ADC platform has consistently demonstrated remarkable preclinical improvements across key metrics of efficacy and safety compared to existing ADC technologies. We are unlocking the long-promised yet elusive potential of antibody-drug conjugates to transform targeted cancer therapy

TWO ADCs DELIVERING TOPOISOMERASE I (TOP1) POISONS (ENHERTU AND TRODELVY) HAVE RECENTLY BEEN FDA-APPROVED FOR HER2- AND TROP2-EXPRESSING SOLID TUMORS

HOW ENHERTU® HER2-DIRECTED ADC WORKS ?

HOW TRODELVY® TROP2-DIRECTED ADC WORKS?

OUR PUBLICATIONS ON ANTIBODY-DRUG CONJUGATES

Selected publications by Dr Borys Shor display the citations in Pubmed

1: Betts AM, Haddish-Berhane N, Tolsma J, Jasper P, King LE, Sun Y, Chakrapani S, Shor B, Boni J, Johnson TR. Preclinical to Clinical Translation of Antibody- Drug Conjugates Using PK/PD Modeling: a Retrospective Analysis of Inotuzumab Ozogamicin. AAPS J. 2016 Sep;18(5):1101-1116. doi: 10.1208/s12248-016-9929-7. Epub 2016 May 19. PMID: 27198897.

2: Shor B, Kahler J, Dougher M, Xu J, Mack M, Rosfjord E, Wang F, Melamud E, Sapra P. Enhanced Antitumor Activity of an Anti-5T4 Antibody-Drug Conjugate in Combination with PI3K/mTOR inhibitors or Taxanes. Clin Cancer Res. 2016 Jan 15;22(2):383-94. doi: 10.1158/1078-0432.CCR-15-1166. Epub 2015 Aug 28. PMID: 26319086.

3. Mack, M., Kahler, J., Shor, B., Ritchie, M., Dougher, M., Sung, M. and Sapra, P. (2016). Lysosomes and Antibody–Drug Conjugates. In Lysosomes: Biology, Diseases, and Therapeutics (eds F.R. Maxfield, J.M. Willard and S. Lu). https://doi.org/10.1002/9781118978320.ch17

4: Shor B, Gerber HP, Sapra P. Preclinical and clinical development of inotuzumab-ozogamicin in hematological malignancies. Mol Immunol. 2015 Oct;67(2 Pt A):107-16. doi: 10.1016/j.molimm.2014.09.014. Epub 2014 Oct 7. PMID: 25304309.

5: He H, Ratnayake AS, Janso JE, He M, Yang HY, Loganzo F, Shor B, O’Donnell CJ, Koehn FE. Cytotoxic Spliceostatins from Burkholderia sp. and Their Semisynthetic Analogues. J Nat Prod. 2014 Aug 22;77(8):1864-70. doi: 10.1021/np500342m. PMID: 25098528.

6: Sapra P, Shor B. Monoclonal antibody-based therapies in cancer: advances and challenges. Pharmacol Ther. 2013 Jun;138(3):452-69. doi: 10.1016/j.pharmthera.2013.03.004. Epub 2013 Mar 15. PMID: 23507041.

Selected publications by Drs Nathan Tumey & Dhaval Shah display the citations in Pubmed

1: Jackson CP, Fang S, Benjamin SR, Alayi T, Hathout Y, Gillen SM, Handel JP, Brems BM, Howe JM, Tumey LN. Evaluation of an ester-linked immunosuppressive payload: A case study in understanding the stability and cleavability of ester- containing ADC linkers. Bioorg Med Chem Lett. 2022 Nov 1;75:128953. doi: 10.1016/j.bmcl.2022.128953. Epub 2022 Sep 1. PMID: 36058468.

2: Fang S, Brems BM, Olawode EO, Miller JT, Brooks TA, Tumey LN. Design and Characterization of Immune-Stimulating Imidazo[4,5-c]quinoline Antibody-Drug Conjugates. Mol Pharm. 2022 Sep 5;19(9):3228-3241. doi: 10.1021/acs.molpharmaceut.2c00392. Epub 2022 Jul 29. PMID: 35904247.

3: Miller JT, Vitro CN, Fang S, Benjamin SR, Tumey LN. Enzyme-Agnostic Lysosomal Screen Identifies New Legumain-Cleavable ADC Linkers. Bioconjug Chem. 2021 Apr 21;32(4):842-858. doi: 10.1021/acs.bioconjchem.1c00124. Epub 2021 Mar 31. PMID: 33788548.

4: Liu S, Shah DK. Physiologically Based Pharmacokinetic Modeling to Characterize the Effect of Molecular Charge on Whole-Body Disposition of Monoclonal Antibodies. AAPS J. 2023 Apr 28;25(3):48. doi: 10.1208/s12248-023-00812-7. PMID: 37118220.

5: Chang HP, Le HK, Shah DK. Pharmacokinetics and Pharmacodynamics of Antibody- Drug Conjugates Administered via Subcutaneous and Intratumoral Routes. Pharmaceutics. 2023 Apr 3;15(4):1132. doi: 10.3390/pharmaceutics15041132. PMID: 37111619.

6: Chang HP, Li Z, Shah DK. Development of a Physiologically-Based Pharmacokinetic Model for Whole-Body Disposition of MMAE Containing Antibody- Drug Conjugate in Mice. Pharm Res. 2022 Jan;39(1):1-24. doi: 10.1007/s11095-021-03162-1. Epub 2022 Jan 19. PMID: 35044590.

7: Bussing D, Sharma S, Li Z, Meyer LF, Shah DK. Quantitative Evaluation of the Effect of Antigen Expression Level on Antibody-Drug Conjugate Exposure in Solid Tumor. AAPS J. 2021 Apr 15;23(3):56. doi: 10.1208/s12248-021-00584-y. PMID: 33856579.23: Chang HP, Cheung YK, Shah DK. Whole-Body Pharmacokinetics and Physiologically Based Pharmacokinetic Model for Monomethyl Auristatin E (MMAE). J Clin Med. 2021 Mar 23;10(6):1332. doi: 10.3390/jcm10061332. PMID: 33807057; PMCID: PMC8004929.