Prostate cancer (PC) is a potentially high-risk disease and the most common cancer in American men. It is a leading cause of cancer-related deaths in men in the US, second only to lung and bronchus cancer. Advanced and metastatic PC is initially treated with androgen deprivation therapy (ADT), but nearly all cases eventually progress to castrate-resistant prostate cancer (CRPC). CRPC is incurable in the metastatic stage but can be slowed by some conventional chemotherapeutics and second-generation ADT, such as enzalutamide and abiraterone. Therefore, novel therapeutic strategies are urgently needed. Prostate-specific membrane antigen (PSMA) is overexpressed in almost all aggressive PCs. PSMA is widely used as a target for PC imaging and drug delivery. Anti-PSMA monoclonal antibodies (mAbs) have been developed as bioligands for diagnostic imaging and targeted PC therapy. However, these mAbs are successfully used in PC imaging and only a few have gone beyond phase-I for targeted therapy. The 5D3 mAb is a novel, high-affinity, and fast-internalizing anti-PSMA antibody. Importantly, 5D3 mAb demonstrates a unique pattern of cellular localization to the centrosome after internalization in PSMA(+) PC3-PIP cells. These characteristics make 5D3 mAb an ideal bioligand to deliver tubulin inhibitors, such as mertansine, to the cell centrosome, leading to mitotic arrest and elimination of dividing PC cells. We have successfully developed a 5D3 mAb- and mertansine (DM1)-based antibody-drug conjugate (ADC) and evaluated it in vitro for binding affinity, internalization, and cytotoxicity. The in vivo therapeutic efficacy of 5D3-DM1 ADC was evaluated in PSMA(+) PC3-PIP and PSMA(-) PC3-Flu mouse models of human PC. This therapeutic study has revealed that this new anti-PSMA ADC can successfully control the growth of PSMA(+) tumors without inducing systemic toxicity.

Department of Molecular and Comparative Pathobiology The Johns Hopkins University School of Medicine 733 N Broadway Baltimore Maryland 21205 United States

Department of Oncology the Sidney Kimmel Comprehensive Cancer Center The Johns Hopkins University School of Medicine 401 N Broadway Baltimore Maryland 21287 United States

Laboratory of Structural Biology Institute of Biotechnology of the Czech Academy of Sciences BIOCEV Prumyslova 595 252 50 Vestec Czech Republic

The James Buchanan Brady Urologic Institute and Department of Urology Johns Hopkins School of Medicine 600 N Wolfe Street Baltimore Maryland 21287 United States

The Russell H Morgan Department of Radiology and Radiological Science The Johns Hopkins University School of Medicine 720 Rutland Avenue Baltimore Maryland 21205 United States

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Siegel RL; Miller KD; Jemal A Cancer Statistics, 2019. Ca—Cancer J. Clin 2019, 69, 7–34. PubMed

Siegel RL; Miller KD; Jemal A Cancer Statistics, 2020. Ca—Cancer J. Clin 2020, 70, 7–30. PubMed

Cho S; Zammarchi F; Williams DG; Havenith CEG; Monks NR; Tyrer P; D’Hooge F; Fleming R; Vashisht K; Dimasi N; et al. Antitumor Activity of Medi3726 (Adct-401), a Pyrrolobenzodiazepine Antibody-Drug Conjugate Targeting Psma, in Preclinical Models of Prostate Cancer. Mol. Cancer Ther 2018, 17, 2176–2186. PubMed

Semenas J; Allegrucci C; Boorjian S; Mongan N; Liao Persson J Overcoming Drug Resistance and Treating Advanced Prostate Cancer. Curr. Drug Targets 2012, 13, 1308–1323. PubMed PMC

Phillips RM; Deek MP; Deweese TL; Tran PT Metastasis-Directed Therapy in Prostate Cancer. Why, When, and How? Oncology, 2019, 33, 394–399. PubMed

Antonarakis ES; Lu C; Wang H; Luber B; Nakazawa M; Roeser JC; Chen Y; Mohammad TA; Chen Y; Fedor HL; et al. Ar-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer. N. Engl. J. Med 2014, 371, 1028–1038. PubMed PMC

Dong L; Zieren RC; Xue W; de Reijke TM; Pienta KJ Metastatic Prostate Cancer Remains Incurable, Why? Asian J. Urol. 2019, 6, 26–41. PubMed PMC

Mangadlao JD; Wang X; McCleese C; Escamilla M; Ramamurthy G; Wang Z; Govande M; Basilion JP; Burda C Prostate-Specific Membrane Antigen Targeted Gold Nanoparticles for Theranostics of Prostate Cancer. ACS Nano 2018, 12, 3714–3725. PubMed PMC

Niaz MO; Sun M; Ramirez-Fort MK; Niaz MJ Prostate-Specific Membrane Antigen Based Antibody-Drug Conjugates for Metastatic Castration-Resistance Prostate Cancer. Cureus 2020, 12, No. e7147. PubMed PMC

Israeli RS; Powell CT; Corr JG; Fair WR; Heston WD Expression of the Prostate-Specific Membrane Antigen. Cancer Res 1994, 54, 1807–1811. PubMed

Lv Q; Yang J; Zhang R; Yang Z; Yang Z; Wang Y; Xu Y; He Z Prostate-Specific Membrane Antigen Targeted Therapy of Prostate Cancer Using a Dupa-Paclitaxel Conjugate. Mol. Pharm 2018, 15, 1842–1852. PubMed

Wright GL Jr.; Mayer Grob B; Haley C; Grossman K; Newhall K; Petrylak D; Troyer J; Konchuba A; Schellhammer PF; Moriarty R Upregulation of Prostate-Specific Membrane Antigen after Androgen-Deprivation Therapy. Urology 1996, 48, 326–334. PubMed

Chang SS Overview of Prostate-Specific Membrane Antigen. Rev. Urol 2004, 6, S13–S18. PubMed PMC

Rajasekaran SA; Anilkumar G; Oshima E; Bowie JU; Liu H; Heston W; Bander NH; Rajasekaran AK A Novel Cytoplasmic Tail Mxxxl Motif Mediates the Internalization of Prostate-Specific Membrane Antigen. Mol. Biol. Cell 2003, 14, 4835–4845. PubMed PMC

Dorff TB; Fanti S; Farolfi A; Reiter RE; Sadun TY; Sartor O The Evolving Role of Prostate-Specific Membrane Antigen-Based Diagnostics and Therapeutics in Prostate Cancer. Am. Soc. Clin. Oncol. Educ. Book 2019, 39, 321–330. PubMed

Giesel FL; Sterzing F; Schlemmer HP; Holland-Letz T; Mier W; Rius M; Afshar-Oromieh A; Kopka K; Debus J; Haberkorn U; et al. Intra-Individual Comparison of (68)Ga-Psma-11-Pet/Ct and Multi-Parametric Mr for Imaging of Primary Prostate Cancer. Eur. J. Nucl. Med. Mol. Imag 2016, 43, 1400–1406. PubMed PMC

Schwarzenboeck SM; Rauscher I; Bluemel C; Fendler WP; Rowe SP; Pomper MG; Asfhar-Oromieh A; Herrmann K; Eiber M Psma Ligands for Pet Imaging of Prostate Cancer. J. Nucl. Med 2017, 58, 1545–1552. PubMed

Kelly J; Amor-Coarasa A; Nikolopoulou A; Kim D; Williams C Jr.; Ponnala S; Babich JW Synthesis and Pre-Clinical Evaluation of a New Class of High-Affinity (18)F-Labeled Psma Ligands for Detection of Prostate Cancer by Pet Imaging. Eur. J. Nucl. Med. Mol. Imag 2017, 44, 647–661. PubMed PMC

Pan M-H; Gao D-W; Feng J; He J; Seo Y; Tedesco J; Wolodzko JG; Hasegawa BH; Franc BL Biodistributions of 177lu- and 111in-Labeled 7e11 Antibodies to Prostate-Specific Membrane Antigen in Xenograft Model of Prostate Cancer and Potential Use of 111in-7e11 as a Pre-Therapeutic Agent for 177lu-7e11 Radioimmunotherapy. Mol. Imag. Biol 2009, 11, 159–166. PubMed PMC

Troyer JK; Beckett ML; Wright GL Jr. Location of Prostate-Specific Membrane Antigen in the Lncap Prostate Carcinoma Cell Line. Prostate 1997, 30, 232–242. PubMed

Horoszewicz JS; Kawinski E; Murphy GP Monoclonal Antibodies to a New Antigenic Marker in Epithelial Prostatic Cells and Serum of Prostatic Cancer Patients. Anticancer Res 1987, 7, 927–935. PubMed

Milowsky MI; Galsky MD; Morris MJ; Crona DJ; George DJ; Dreicer R; Tse K; Petruck J; Webb IJ; Bander NH; et al. Phase 1/2 Multiple Ascending Dose Trial of the Prostate-Specific Membrane Antigen-Targeted Antibody Drug Conjugate Mln2704 in Metastatic Castration-Resistant Prostate Cancer. Urol. Oncol 2016, 34, 530.e515–530.e521. PubMed PMC

Banerjee SR; Kumar V; Lisok A; Plyku D; Nováková Z; Brummet M; Wharram B; Barinka C; Hobbs R; Pomper MG Evaluation of (111)in-Dota-5d3, a Surrogate Spect Imaging Agent for Radioimmunotherapy of Prostate-Specific Membrane Antigen. J. Nucl. Med 2019, 60, 400–406. PubMed PMC

Nováková Z; Foss CA; Copeland BT; Morath V; Baranová P; Havlínová B; Skerra A; Pomper MG; Barinka C Novel Monoclonal Antibodies Recognizing Human Prostate-Specific Membrane Antigen (Psma) as Research and Theranostic Tools. Prostate 2017, 77, 749–764. PubMed PMC

Hapuarachchige S; Huang CT; Donnelly MC; Bařinka C; Lupold SE; Pomper MG; Artemov D Cellular Delivery of Bioorthogonal Pretargeting Therapeutics in Psma-Positive Prostate Cancer. Mol. Pharm 2020, 17, 98–108. PubMed PMC

Kupchan SM; Komoda Y; Court WA; Thomas GJ; Smith RM; Karim A; Gilmore CJ; Haltiwanger RC; Bryan RF Tumor inhibitors. LXXIII. Maytansine, a Novel Antileukemic Ansa Macrolide from Maytenus Ovatus. J. Am. Chem. Soc 1972, 94, 1354–1356. PubMed

Peddi PF; Hurvitz SA Trastuzumab Emtansine: The First Targeted Chemotherapy for Treatment of Breast Cancer. Future Oncol 2013, 9, 319–326. PubMed PMC

Kupchan SM; Komoda Y; Branfman AR; Sneden AT; Court WA; Thomas GJ; Hintz HPJ; Smith RM; Karim A; Howie GA; et al. Tumor inhibitors. 122. The Maytansinoids. Isolation, Structural Elucidation, and Chemical Interrelation of Novel Ansa Macrolides. J. Org. Chem 1977, 42, 2349–2357. PubMed

Lopus M Antibody-Dm1 Conjugates as Cancer Therapeutics. Canc. Lett 2011, 307, 113–118. PubMed PMC

Lopus M; Oroudjev E; Wilson L; Wilhelm S; Widdison W; Chari R; Jordan MA Maytansine and Cellular Metabolites of Antibody-Maytansinoid Conjugates Strongly Suppress Microtubule Dynamics by Binding to Microtubules. Mol. Cancer Ther 2010, 9, 2689–2699. PubMed PMC

Rong L; Zhou S; Liu X; Li A; Jing T; Liu X; Zhang Y; Cai S; Tang X Trastuzumab-Modified Dm1-Loaded Nanoparticles for Her2(+) Breast Cancer Treatment: An in Vitro and in Vivo Study. Artif. Cells, Nanomed., Biotechnol 2018, 46, 1708–1718. PubMed

Zimmerman ME; Meyer AR; Rowe SP; Gorin MA Imaging of Prostate Cancer with Positron Emission Tomography. Clin. Adv. Hematol. Oncol 2019, 17, 455–463. PubMed

Rowe SP; Drzezga A; Neumaier B; Dietlein M; Gorin MA; Zalutsky MR; Pomper MG Prostate-Specific Membrane Antigen-Targeted Radiohalogenated Pet and Therapeutic Agents for Prostate Cancer. J. Nucl. Med 2016, 57, 90S–96S. PubMed PMC

Current K; Meyer C; Magyar CE; Mona CE; Almajano J; Slavik R; Stuparu AD; Cheng C; Dawson DW; Radu CG; et al. Investigating Psma-Targeted Radioligand Therapy Efficacy as a Function of Cellular Psma Levels and Intratumoral Psma Heterogeneity. Clin. Cancer Res 2020, 26, 2946–2955. PubMed PMC

Müller C; Umbricht CA; Gracheva N; Tschan VJ; Pellegrini G; Bernhardt P; Zeevaart JR; Koster U; Schibli R; van der Meulen NP Terbium-161 for Psma-Targeted Radionuclide Therapy of Prostate Cancer. Eur. J. Nucl. Med. Mol. Imag 2019, 46, 1919–1930. PubMed PMC

Phillips GDL; Li G; Dugger DL; Crocker LM; Parsons KL; Mai E; Blattler WA; Lambert JM; Chari RV; Lutz RJ; et al. Targeting Her2-Positive Breast Cancer with Trastuzumab-Dm1, an Antibody-Cytotoxic Drug Conjugate. Cancer Res 2008, 68, 9280–9290. PubMed

Machulkin AE; Ivanenkov YA; Aladinskaya AV; Veselov MS; Aladinskiy VA; Beloglazkina EK; Koteliansky VE; Shakhbazyan AG; Sandulenko YB; Majouga AG Small-Molecule Psma Ligands. Current State, Sar and Perspectives. J. Drug Target 2016, 24, 679–693. PubMed

Hapuarachchige S; Kato Y; Artemov D Bioorthogonal Two-Component Drug Delivery in Her2(+) Breast Cancer Mouse Models. Sci. Rep 2016, 6, 24298. PubMed PMC

Hapuarachchige S; Zhu W; Kato Y; Artemov D Bioorthogonal, Two-Component Delivery Systems Based on Antibody and Drug-Loaded Nanocarriers for Enhanced Internalization of Nanotherapeutics. Biomaterials 2014, 35, 2346–2354. PubMed PMC

Haun JB; Devaraj NK; Hilderbrand SA; Lee H; Weissleder R Bioorthogonal Chemistry Amplifies Nanoparticle Binding and Enhances the Sensitivity of Cell Detection. Nat. Nanotechnol 2010, 5, 660–665. PubMed PMC

Galsky MD; Eisenberger M; Moore-Cooper S; Kelly WK; Slovin SF; DeLaCruz A; Lee Y; Webb IJ; Scher HI Phase I Trial of the Prostate-Specific Membrane Antigen-Directed Immunoconjugate Mln2704 in Patients with Progressive Metastatic Castration-Resistant Prostate Cancer. J. Clin. Oncol 2008, 26, 2147–2154. PubMed

Kobayashi H; Choyke PL Super Enhanced Permeability and Retention (Supr) Effects in Tumors Following near Infrared Photoimmunotherapy. Nanoscale 2016, 8, 12504–12509. PubMed PMC

Nakamura Y; Mochida A; Choyke PL; Kobayashi H Nanodrug Delivery: Is the Enhanced Permeability and Retention Effect Sufficient for Curing Cancer? Bioconjugate Chem. 2016, 27, 2225–2238. PubMed PMC

Lee SY; Ju MK; Jeon HM; Jeong EK; Lee YJ; Kim CH; Park HG; Han SI; Kang HS Regulation of Tumor Progression by Programmed Necrosis. Oxid. Med. Cell. Longevity 2018, 2018, 3537471. PubMed PMC

Tomes L; Emberley E; Niu Y; Troup S; Pastorek J; Strange K; Harris A; Watson PH Necrosis and Hypoxia in Invasive Breast Carcinoma. Breast Canc. Res. Treat 2003, 81, 61–69. PubMed

Cheville JC; Lohse CM; Zincke H; Weaver AL; Blute ML Comparisons of Outcome and Prognostic Features among Histologic Subtypes of Renal Cell Carcinoma. Am. J. Surg. Pathol 2003, 27, 612–624. PubMed

Jin S; DiPaola RS; Mathew R; White E Metabolic Catastrophe as a Means to Cancer Cell Death. J. Cell Sci 2007, 120, 379–383. PubMed PMC

Development and therapeutic evaluation of 5D3(CC-MLN8237)3.2 antibody-theranostic conjugates for PSMA-positive prostate cancer therapy

Targeting Prostate Cancer Using Bispecific T-Cell Engagers against Prostate-Specific Membrane Antigen

A prostate-specific membrane antigen activated molecular rotor for real-time fluorescence imaging

Engineered Fragments of the PSMA-Specific 5D3 Antibody and Their Functional Characterization