PD­Cs vs. AD­Cs: A New Fron­tier in Tar­get­ed Can­cer Ther­a­pies and the Po­ten­tial for De­vel­op­ment Part­ner­ships

As an­ti­body–drug con­ju­gates (AD­Cs) and im­mune check­point in­hibitors con­tin­ue to grab a lot of at­ten­tion as trans­for­ma­tive can­cer ther­a­pies, they would ap­pear to leave lit­tle room for oth­er treat­ment modal­i­ties. Yet if pre­clin­i­cal and ear­ly clin­i­cal tri­als are any in­di­ca­tion, pep­tide–drug con­ju­gates (PD­Cs) could be­come the Next Big Thing in on­col­o­gy, po­ten­tial­ly ush­er­ing in a new wave of promis­ing R&D pro­grams.

The po­ten­tial of PD­Cs large­ly stems from their pur­port­ed ad­van­tages over AD­Cs. De­spite their suc­cess, AD­Cs’ clin­i­cal ben­e­fit and du­ra­tion of ob­jec­tive re­sponse are lim­it­ed by the emer­gence of re­sis­tance mech­a­nisms¹, their large size, and their rel­a­tive­ly long half-life, which can in­crease the risk of neu­trope­nia, neu­ropa­thy, he­pa­to­tox­i­c­i­ty, and oth­er off-tar­get ef­fects.^2,3 Most AD­Cs are fur­ther lim­it­ed by their slow in­ter­nal­iza­tion in­to the tar­get cell (6 to 14 hours⁴), leav­ing them on the cell sur­face for an ex­tend­ed pe­ri­od and re­duc­ing the vol­ume of drug that reach­es the in­tra­cel­lu­lar tar­get; this lim­i­ta­tion ne­ces­si­tates con­ju­ga­tion with high­ly tox­ic drugs.⁵ Con­se­quent­ly, there re­mains a de­mand for pre­cise­ly tar­get­ed ther­a­pies with more fa­vor­able tol­er­a­bil­i­ty pro­files and for im­proved de­liv­ery sys­tems that en­able safe and ef­fec­tive com­bi­na­tion treat­ments.

PD­Cs— ther­a­pies that use a cleav­able or non-cleav­able link­er to at­tach a re­cep­tor-tar­get­ing pep­tide to a drug pay­load — ap­pear poised to meet that need. Com­pared to AD­Cs, PD­Cs are small, ag­ile chem­i­cal en­ti­ties, some with half-lives of a few hours and tar­gets that are en­abling rapid in­ter­nal­iza­tion and im­proved tu­mor pen­e­tra­tion. Those prop­er­ties may al­low for sus­tained, ro­bust an­ti­cancer ac­tiv­i­ty, an im­proved safe­ty pro­file, and con­ju­ga­tion with dif­fer­ent pay­loads.^6,7 PD­Cs al­so ap­pear able to by­pass drug re­sis­tance mech­a­nisms and en­hance im­mune check­point in­hi­bi­tion.⁷ Ad­di­tion­al­ly, com­pared to mon­o­clon­al an­ti­bod­ies, PD­Cs are less ex­pen­sive to pro­duce, faster to ad­vance from pre­clin­i­cal to clin­i­cal de­vel­op­ment, and of­fer en­hanced tu­mor pen­e­tra­tion as well as greater flex­i­bil­i­ty in terms of ease of pay­load-switch­ing.⁸

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SORT1: Op­ti­miz­ing Tar­get Se­lec­tion

Sor­til­in (SORT1), a trans­mem­brane gly­co­pro­tein of the vas­cu­lar pro­tein sort­ing 10 pro­tein (Vsp10p) fam­i­ly, epit­o­mizes the promise of PDC ther­a­py. SORT1 nor­mal­ly func­tions as a cel­lu­lar shut­tle sys­tem to trans­port pro­teins across the cell mem­brane and to rapid­ly in­ter­nal­ize them via the en­do­so­mal/lyso­so­mal path­way. SORT1 is high­ly ex­pressed in many sol­id tu­mors, in­clud­ing ovar­i­an, en­dome­tri­al, and breast can­cers^9-11, and is as­so­ci­at­ed with tu­mori­ge­n­e­sis, re­sis­tance, pro­gres­sion, ad­vanced dis­ease, poor prog­no­sis, and re­duced sur­vival out­comes in can­cer. Its at­trac­tive­ness as a re­search tar­get is fur­ther en­hanced by its high­er ex­pres­sion in can­cer cells com­pared to nor­mal cells.

SORT1-tar­get­ing PDC ther­a­py lever­ages the nat­ur­al in­ter­nal­iza­tion func­tion of SORT1 to pro­mote rapid in­ter­nal­iza­tion and de­liv­ery of a cy­to­tox­ic pay­load di­rect­ly in­to can­cer cells, while lim­it­ing lig­and degra­da­tion in the cir­cu­la­tion as well as off-tar­get tox­i­c­i­ty.¹² By rapid­ly in­ter­nal­iz­ing its nat­ur­al lig­ands (e.g., pro­gran­ulin, neu­rotensin), and with a half-life of 4 min­utes,¹³ SORT1 ex­pe­dites pep­tide up­take with­in can­cer cells.¹⁴

SORT1-Tar­get­ed PDC De­liv­ers Cy­to­tox­ic Pay­load Di­rect­ly In­to Can­cer Cells

Ev­i­dence of the Vi­a­bil­i­ty of PD­Cs in An­ti­cancer Ther­a­py

Ther­at­e­ch­nolo­gies has es­tab­lished the SORT1+ Tech­nol­o­gy™ plat­form as an en­gine for the de­vel­op­ment of PD­Cs that tar­get SORT1. The plat­form re­lies on the use of a nov­el, pro­pri­etary pep­tide called TH19P01, which can be con­ju­gat­ed to nu­mer­ous well-char­ac­ter­ized an­ti­cancer drugs.

Pre­clin­i­cal da­ta pre­sent­ed ear­li­er this year at the Amer­i­can As­so­ci­a­tion for Can­cer Re­search (AACR) an­nu­al meet­ing demon­strat­ed that our in­ves­ti­ga­tion­al camp­tothecin-pep­tide con­ju­gates are well tol­er­at­ed and as­so­ci­at­ed with sig­nif­i­cant tu­mor re­gres­sion in col­orec­tal can­cer (CRC) xenograft mod­els. In one ex­per­i­ment, SORT1 gene si­lenc­ing in­hib­it­ed camp­tothecin-con­ju­gate up­take in hu­man HT-29 col­orec­tal ade­no­car­ci­no­ma cells, sug­gest­ing that these PD­Cs en­ter can­cer cells via a SORT-1 me­di­at­ed in­ter­nal­iza­tion process. In oth­er ex­per­i­ments, three PD­Cs – TH2101, TH2205, and TH2310 – that car­ry a cy­to­tox­ic pay­load of SN-38, the ac­tive metabo­lite of irinote­can, ex­ert­ed greater an­ti-pro­lif­er­a­tive ac­tiv­i­ties against CRC cells in mice, com­pared to un­con­ju­gat­ed irinote­can. In two dif­fer­ent CRC xenograft mod­els, as well as in a triple-neg­a­tive breast can­cer (TNBC) xenograft mod­el, a fourth PDC, TH2303, which car­ries an ex­ate­can pay­load, was as­so­ci­at­ed with in­creased tu­mor growth in­hi­bi­tion and greater tol­er­a­bil­i­ty com­pared to un­con­ju­gat­ed ex­ate­can or irinote­can.¹⁵

Ad­di­tion­al­ly, the com­bi­na­tion of two SORT1-tar­get­ing PD­Cs – su­do­c­etax­el zen­du­sor­tide and TH2101, which have a syn­er­gis­tic an­ti-tu­mor ef­fect at re­duced dos­es – led to in­creased tu­mor growth in­hi­bi­tion and some com­plete re­spons­es in the HT-29 xenograft mod­el, com­pared to ei­ther PDC ad­min­is­tered alone; the com­bi­na­tion al­so was well tol­er­at­ed.¹⁵ The sig­nif­i­cant tu­mor re­gres­sion fol­low­ing com­bi­na­tion ther­a­py is no­table be­cause the HT-29 xenograft mod­el is no­to­ri­ous for its re­sis­tance to mul­ti­ple cy­to­tox­ic drugs.

More than 50 pa­tients with ad­vanced sol­id tu­mors have been dosed with su­do­c­etax­el zen­du­sor­tide (TH1902) as part of a Phase 1 clin­i­cal tri­al in mul­ti­ple tu­mor types.  An up­dat­ed analy­sis from Parts 1 and 2 of the tri­al, pre­sent­ed at the 2024 Amer­i­can So­ci­ety of Clin­i­cal On­col­o­gy (AS­CO) an­nu­al meet­ing, showed that su­do­c­etax­el zen­du­sor­tide in­duced durable dis­ease sta­bi­liza­tion (up to 45 weeks) last­ing be­yond treat­ment com­ple­tion. Re­sults sug­gest a unique, mul­ti­modal mech­a­nism of ac­tion dis­tinct from oth­er can­cer ther­a­peu­tics, in­clud­ing in­duc­tion of im­mune cell in­fil­tra­tion even in “cold” tu­mor mod­els, in­hi­bi­tion of vas­cu­lo­genic mim­ic­ry, tar­get­ing of chemother­a­py-re­sis­tant can­cer stem cells, and ac­ti­va­tion of the cGAS/STING im­mune path­way, among oth­er ac­tions.¹⁶ Part 3 of the Phase 1 tri­al is cur­rent­ly un­der­way in pa­tients with ad­vanced ovar­i­an can­cer.

A Po­ten­tial Pro­fu­sion of Con­ju­gates In­clud­ing Ra­dioiso­topes

The ver­sa­til­i­ty of the SORT1+ Tech­nol­o­gy™ plat­form may en­able de­vel­op­ment of fol­low-on con­ju­gates that take ad­van­tage of the in­ter­nal­iza­tion prop­er­ties of the SORT1 re­cep­tor. In par­tic­u­lar, those prop­er­ties ap­pear to make SORT1 a suit­able tar­get for ra­dioiso­tope con­ju­gates, in that the re­cep­tor’s abil­i­ty to pro­mote rapid in­ter­nal­iza­tion would ap­pear to fa­cil­i­tate en­try of a ra­dioiso­tope in­to tar­get tu­mor cells while lim­it­ing im­pact on oth­er, non-can­cer­ous tis­sues.

Ra­dioiso­topes are just one ex­am­ple of the kinds of next-gen­er­a­tion con­ju­gates that could emerge from SORT1-di­rect­ed re­search ef­forts and po­ten­tial de­vel­op­ment part­ner­ships lever­ag­ing our PDC plat­form. The util­i­ty of con­ju­gate-based an­ti­cancer ther­a­py is spurring op­por­tu­ni­ties for col­lab­o­ra­tion be­tween biotech­nol­o­gy and phar­ma­ceu­ti­cal com­pa­nies both large and small, with some com­pa­nies bas­ing their en­tire pipelines on such mod­els.

Those pos­si­bil­i­ties have made PD­Cs and their fol­low-on com­pounds a cat­e­go­ry to watch.

 Ref­er­ences

1. Bio­phar­ma PEG. Overview of ADC-Based Com­bi­na­tion Ther­a­pies; 2023. https://www.biochempeg.com/ar­ti­cle/330.html
2. Hin­richs MJM, Dix­it R. An­ti­body Drug Con­ju­gates: Non­clin­i­cal Safe­ty Con­cerns. AAPS J. 2015;17(5):1055-1064.
3. Mck­er­tish CM, Kayser V. Ad­vances and Lim­i­ta­tions of An­ti­body Drug Con­ju­gates for Can­cer. 2021;9:872.
4. Maass KF, Kulka­rni C, Betts AM, Wit­trup KD. De­ter­mi­na­tion of Cel­lu­lar Pro­cess­ing Rates for a Trastuzum­ab-May­tansi­noid An­ti­body-Drug Con­ju­gate (ADC) High­lights Key Pa­ra­me­ters for ADC De­sign. AAPS J. 2016;18(3):635-646.
5. Ne­jad­moghad­dam MR, Mi­nai-Tehrani A, Ghahre­man­zadeh R, Mah­mou­di M, Di­nar­vand R, Zarnani AH. An­ti­body-Drug Con­ju­gates: Pos­si­bil­i­ties and Chal­lenges. Avi­cen­na J Med Biotech. 2019;11(1): 3-23.
6. Wu M, Huang W, Yang N, Liu Y. Learn from An­ti­body-Drug Con­ju­gates: Con­sid­er­a­tion in the Fu­ture Con­struc­tion of Pep­tide-Drug Con­ju­gates for Can­cer Ther­a­py. Exp Hema­tol On­col. 2022;11:93.
7. Chav­da VP, Solan­ki HK, David­son M, Apos­tolopou­los V, Bo­jars­ka J. Pep­tide-Drug Con­ju­gates: A New Hope for Can­cer Man­age­ment. 2022;27:7232.
8. Alas M, Saghaei­dehko­r­di A, Kaur K. Pep­tide-Drug Con­ju­gates with Dif­fer­ent Link­ers for Can­cer Ther­a­py. J Med Chem. 2021;64(1):216-232.
9. Ghaemi­manesh F, Ah­ma­di­an G, Talebi S, et al. The Ef­fect of Sor­til­in Si­lenc­ing on Ovar­i­an Car­ci­no­ma Cells.Avi­cen­na J. Med. Biotech­nol. 2014;6:169–177.
10. Hem­mati S, Zarnani AH, Mah­mou­di AR, et al. Ec­topic Ex­pres­sion of Sor­til­in 1 (NTR-3) in Pa­tients with Ovar­i­an Car­ci­no­ma.Avi­cen­na J. Med. Biotech­nol. 2009;1:125–131. 
11. Berg­er K, Rhost S, Rafns­dót­tir S, et al. Tu­mor Co-Ex­pres­sion of Pro­gran­ulin and Sor­til­in as a Prog­nos­tic Bio­mark­er in Breast Can­cer.BMC Can­cer. 2021;21:185.
12. De­meule M, Cur­rie JC, Larocque A, et al. In­creas­ing Pen­e­tra­tion of An­ti­cancer Drugs through Sor­til­in Re­cep­tor-Me­di­at­ed Can­cer Ther­a­py: A New Tar­get­ed and Per­son­al­ized Ap­proach in the Treat­ment of Ovar­i­an Can­cer. Can­cer Res. 2017;77(13 sup­pl): 5146.
13. Hu F, Padukkavi­dana T, Vægter CB, et al. Sor­til­in-Me­di­at­ed En­do­cy­to­sis De­ter­mines Lev­els of the Fron­totem­po­ral De­men­tia Pro­tein, Pro­gran­ulin. 2010;68:654-667.
14. Regi­na A, De­meule M, Tri­pa­thy S, et al. ANG4043, a Nov­el Brain-Pen­e­trant Pep­tide-mAb Con­ju­gate, is Ef­fi­ca­cious against HER2-Pos­i­tive In­tracra­nial Tu­mors in Mice. Mol Can­cer Ther. 2015;14:129-140.
15. Das SK, Cur­rie JC, De­meule M, et al. Pre-clin­i­cal Ev­i­dence for New Camp­tothecin-Pep­tide Con­ju­gates in the Treat­ment of Sor­til­in-Pos­i­tive Col­orec­tal Can­cer. Pre­sent­ed at 2024 an­nu­al meet­ing of the Amer­i­can As­so­ci­a­tion for Can­cer Re­search (AACR), San Diego, CA, April 8, 2024, Poster #2071.
16. Win­er I, Barve M, Shah S, et al. Long-Term Ef­fi­ca­cy, Safe­ty and PK Da­ta of TH1902 (Su­do­c­etax­el Zen­du­sor­tide), a Nov­el SORT1-Tar­get­ing Pep­tide-Drug Con­ju­gate (PDC). Pre­sent­ed at 2024 an­nu­al meet­ing of the Amer­i­can So­ci­ety of Clin­i­cal On­col­o­gy (AS­CO), Chica­go, IL, May 23, 2024, Ab­stract #3081, Poster #226.