Im­muno-On­col­o­gy 2.0: How Re­gen­eron is Uti­liz­ing its Ex­per­tise in An­ti­bod­ies to Lead the Next Wave of Com­bi­na­to­r­i­al Ap­proach­es in Can­cer Care

Amaz­ing­ly, it is on­ly a lit­tle more than a decade since the first ap­proval of a check­point block­ade an­ti­body for the treat­ment of can­cer, which has led to a par­a­digm shift in can­cer treat­ment.¹ Pri­or to that, de­spite pri­or oc­ca­sion­al suc­cess­es, there was a great deal of skep­ti­cism that the im­mune sys­tem could be har­nessed to bat­tle ma­lig­nan­cy.² Now im­munother­a­py (in­clud­ing check­point in­hibitors, tu­mor-tar­get­ed CD3 bis­pecifics, per­son­al­ized cel­lu­lar ther­a­pies, and oth­er modal­i­ties) is ac­cept­ed as a fun­da­men­tal pil­lar of can­cer care, along­side surgery, ra­di­a­tion and chemother­a­py.^1,3

While re­cent ad­vances in the field of im­muno-on­col­o­gy have been trans­for­ma­tion­al, sig­nif­i­cant un­met need re­mains for new can­cer treat­ments that in­crease sur­vival, re­duce pro­gres­sion and im­prove qual­i­ty of life for pa­tients.¹

The Uni­verse of Im­mune On­col­o­gy Ap­proach­es

Ap­proach­es to aug­ment­ing the im­mune re­sponse to fight can­cer range from those that di­rect­ly en­hance spe­cif­ic an­ti-tu­mor anti­gen re­ac­tiv­i­ty to those that in­di­rect­ly aug­ment im­mune sys­tem func­tion.

Clas­sic ex­am­ples of the di­rect ap­proach are tu­mor in­fil­trat­ing lym­pho­cytes (TILs) that were hy­poth­e­sized to be en­riched in T cells that rec­og­nize tu­mor anti­gens. The iso­la­tion of TILs or pe­riph­er­al T cells, ex­pan­sion with/with­out gene en­gi­neer­ing, and re­turn to pa­tients is a vari­a­tion of di­rect­ed per­son­al­ized cel­lu­lar ther­a­pies that have been ap­proved or are in de­vel­op­ment.⁴ Per­son­al­ized cel­lu­lar im­munother­a­pies have gar­nered sub­stan­tial at­ten­tion in the past few years.

Ex­am­ples of in­di­rect ap­proach­es in­clude the orig­i­nal “Co­ley’s tox­ins,” cy­tokine based ther­a­pies such as high-dose in­ter­leukin 2 or, most promi­nent­ly, check­point block­ade, par­tic­u­lar­ly CT­LA-4 as the first to reach the mar­ket fol­lowed close­ly by PD-1/PD-1 lig­and (PD-L1) based treat­ments.^5,6 Check­point in­hibitors help re­lease the brakes that tu­mor cells ex­ploit to pre­vent the sys­tem from re­act­ing to them and fur­ther en­hance the abil­i­ty of im­mune cells to rec­og­nize and elim­i­nate those can­cer cells from the body.⁷ Some tu­mors ex­press sig­nif­i­cant amounts of PD-L1, which in­ter­acts with the PD-1 re­cep­tor on cy­to­tox­ic T cells to block T cell ac­ti­va­tion. An­ti-PD-1 and an­ti-PDL1 ther­a­pies block the PD-1 and an­ti-PD-L1 re­cep­tors on the T cells, re­spec­tive­ly, thus re-en­abling T cell ac­ti­va­tion against the can­cer cells. An­ti-PD-1 treat­ments have been ap­proved both as a monother­a­py, as well as part of com­bi­na­tion ther­a­pies, ir­re­spec­tive of PD-L1 ex­pres­sion, for a va­ri­ety of can­cers.⁸ Par­tic­u­lar­ly, an­ti-PD-1 ther­a­pies are now a cor­ner­stone in can­cer treat­ment due to their abil­i­ty to help over­come one of tu­mors’ great­est sur­vival mech­a­nisms: sup­pres­sion of the im­mune sys­tem.^1,9

Be­tween the poles of di­rect and in­di­rect mech­a­nisms lie new­er ef­forts to fo­cus im­mune ac­ti­va­tion to­wards tu­mor anti­gens, in­clud­ing tu­mor vac­cines, pro­tein ther­a­peu­tics such as CD3 bis­pecifics, or tu­mor tar­get­ed cy­tokines. In par­tic­u­lar, CD3 redi­rect­ing bis­pe­cif­ic agents bridge tu­mor anti­gens to T cells and have been ap­proved in sev­er­al hema­to­log­ic ma­lig­nan­cies and are in de­vel­op­ment in sol­id tu­mors.^9,10

Re­gen­eron’s Ap­proach to On­col­o­gy

A ma­jor fo­cus of our re­search is to bet­ter har­ness and com­ple­ment the im­mune sys­tem’s mech­a­nisms for tar­get­ing and elim­i­nat­ing can­cer cells with greater speci­fici­ty while spar­ing as many healthy cells as pos­si­ble. Re­gen­eron rec­og­nizes that one of the key prin­ci­ples for suc­cess­ful de­ploy­ment of the im­mune sys­tem is mul­ti-tar­get­ing, the no­tion that mul­ti­ple ef­fec­tor arms or speci­fici­ties in com­bi­na­tion will be re­quired for op­ti­mal and durable an­ti-tu­mor ac­tiv­i­ty. This is a les­son learned from the os­ten­si­ble orig­i­nal pur­pose of the im­mune sys­tem, name­ly, to pro­tect or­gan­isms from in­fec­tious pathogens.^1,11

Re­gen­eron’s tra­di­tion of physi­cian-sci­en­tist lead­er­ship and deep knowl­edge of hu­man bi­ol­o­gy guides us to look at can­cer dif­fer­ent­ly than oth­er bio­phar­ma­ceu­ti­cal com­pa­nies, fol­low­ing the sci­ence to fu­el con­tin­ued in­no­va­tion and en­able the de­vel­op­ment of nov­el com­bi­na­to­r­i­al ther­a­pies. We are ac­tive­ly work­ing to har­ness the body’s nat­ur­al abil­i­ties to fight can­cer via the im­mune sys­tem in new ways.
In par­tic­u­lar, we in­vest­ed in de­vel­op­ing a toolk­it of agents that tar­get dif­fer­ent as­pects of the im­mune sys­tem and lend them­selves to facile com­bi­na­tions with the goal of de­ploy­ing the most po­tent im­mune ef­fec­tor re­spons­es against can­cer.

Lay­ing the Foun­da­tion with An­ti-PD-1 Re­search

Re­gen­eron ini­ti­at­ed ef­forts re­search­ing the PD-1 path­way, and we have ap­plied this ex­pe­ri­ence to iden­ti­fy ad­di­tion­al in­ves­ti­ga­tion­al path­ways with the po­ten­tial to ad­dress un­met med­ical need.

Re­search fo­cused on PD-1 in­hi­bi­tion has made great strides in over­com­ing the im­muno­sup­pres­sive mech­a­nisms of can­cer cells, and com­bi­na­tion ther­a­pies have pro­gressed our un­der­stand­ing of how to har­ness the im­mune sys­tem’s abil­i­ties to fight can­cer. We be­lieve there is more to be done.¹ We are cur­rent­ly de­vel­op­ing ad­di­tion­al com­bi­na­tions of check­point in­hibitors and bis­pecifics.

Build­ing a Fu­ture of Im­munother­a­py with Bis­pe­cif­ic An­ti­body Ap­proach­es

Bis­pe­cif­ic an­ti­bod­ies uti­lize the mul­ti-tar­get­ing func­tion of an­ti­bod­ies to en­hance ex­ist­ing meth­ods of can­cer cell de­struc­tion.¹ Re­gen­eron’s Ve­loci-Bi® plat­form builds up­on our an­ti­body ex­per­tise and al­lows us to cre­ate full-length bis­pe­cif­ic an­ti­bod­ies with no link­ers or ar­ti­fi­cial se­quences.¹² Bis­pe­cif­ic an­ti­bod­ies can thus be gen­er­at­ed to bind to a tar­get of choice, such as a tu­mor cell mark­er, and man­u­fac­tured as a po­ten­tial an­ti-can­cer ther­a­peu­tic. Due to the ab­sence of ar­ti­fi­cial link­ers, the bis­pe­cif­ic an­ti­bod­ies mim­ic the struc­ture and func­tion of mon­o­clon­al an­ti­bod­ies but bind to mul­ti­ple tar­gets to en­hance im­mune sys­tem func­tion and tar­get­ed de­struc­tion of can­cer cells.^1,13

Be­ing able to re­search these mul­ti­ple path­ways un­der one roof pro­vides flex­i­bil­i­ty to eas­i­ly ex­plore dif­fer­ent com­bi­na­tion ap­proach­es.

De­liv­er­ing on the Clin­i­cal Po­ten­tial in On­col­o­gy

For 35 years, Re­gen­eron has re­mained stead­fast in our mis­sion to use the pow­er of sci­ence to re­peat­ed­ly bring new, life-trans­form­ing med­i­cines to pa­tients. We’re ap­ply­ing this end-to-end for­mu­la to on­col­o­gy, with the goal of rev­o­lu­tion­iz­ing the way can­cer is treat­ed. We are pur­su­ing re­search with the goal of en­hanc­ing the nat­ur­al func­tions of the hu­man im­mune sys­tem to fight can­cer.

Ul­ti­mate­ly, we are proud to stand at the fore­front of in­no­va­tion for nov­el treat­ments in on­col­o­gy and are com­mit­ted to uti­liz­ing ther­a­peu­tic flex­i­bil­i­ty to pi­o­neer po­ten­tial new so­lu­tions for pre­vi­ous­ly un­treat­able can­cers.

Ref­er­ences

¹Dahlen E, Veiton­ma­ki N, Norlen P. Bis­pe­cif­ic an­ti­bod­ies in can­cer im­munother­a­py. Ther Adv Vac­cines Im­munother. 2018; 6(1):3–17. doi: 10.1177/2515135518763280
²Do­bosz P, Dzieciątkows­ki T. The In­trigu­ing His­to­ry of Can­cer Im­munother­a­py. Front Im­munol. 2019; 10:2965. doi: 10.3389/fim­mu.2019.02965
³Na­tion­al Can­cer In­sti­tute. Im­munother­a­py to Treat Can­cer. Pub­lished Sep­tem­ber 24, 2019. Ac­cessed April 9, 2023. www.can­cer.gov/about-can­cer/treat­ment/types/im­munother­a­py
⁴Pai­jens S, Vled­der A, Bruyn M, Ni­j­man H. Tu­mor-in­fil­trat­ing lym­pho­cytes in the im­munother­a­py era. Cell Mol Im­munol. 2020;18(4):842–859. doi: 10.1038/s41423-020-00565-9
⁵Asao, H. In­ter­leukin-2. Ref­er­ence Mod­ule in Bio­med­ical Sci­ences. 2014. doi: 10.1016/B978-0-12-801238-3.040587
⁶Sze­to G, Fin­ley S. In­te­gra­tive Ap­proach­es to Can­cer Im­munother­a­py. Trends Can­cer. 2019;5(7);400-410. doi: 10.1016/j.tre­can.2019.05.010.
⁷Pa­paioan­nou, NE, Be­ni­a­ta, OV, Vit­sos P, Tsit­silo­nis O, Sama­ra P. Har­ness­ing the im­mune sys­tem to im­prove can­cer ther­a­py. An­nals of Trans­la­tion­al Med­i­cine. 2016;4(14):261–261. doi.org/10.21037/atm.2016.04.01
⁸Jiang H, Ni H, Zhang P, Guo X, Wu M, Shen H, et al. On­coim­munol­o­gy, 10(1), 1943180. Doi: 10.1080/2162402X.2021.1943180
⁹KC, Miljkovic MD, Walkd­mann TA. Cy­tokines in the Treat­ment of Can­cer. J In­ter­fer­on Cy­tokine Res. 2019;39(1):6–21. doi: 10.1089/jir.2018.0019
¹⁰Benon­is­son H, Al­t­in­tas I, Slui­jter M, Ver­ploe­gen S, Labri­jn AF, Schu­urhuis DH, et al. CD3-Bis­pe­cif­ic An­ti­body Ther­a­py Turns Sol­id Tu­mors in­to In­flam­ma­to­ry Sites but Does Not In­stall Pro­tec­tive Mem­o­ry. Mol Can­cer Ther. 2019;18(2):312–322. doi: 10.1158/1535-7163.MCT-18-0679
¹¹Pe­trel­li A, Gior­dano S. From sin­gle- to mul­ti-tar­get drugs in can­cer ther­a­py: when as­peci­fici­ty be­comes an ad­van­tage. Cur­rent Med­i­c­i­nal Chem­istry. 2008;15(5):422-432. doi: 10.2174/092986708783503212
¹²Da­ta on file. Re­gen­eron.com: Tech­nol­o­gy.
¹³Wu Z, Che­ung NV. T cell en­gag­ing bis­pe­cif­ic an­ti­body (T-BsAb): From tech­nol­o­gy to ther­a­peu­tics. Phar­ma­col­o­gy & Ther­a­peu­tics. 2018; 182:161–175. Doi: 10.1016/j.pharmthera.2017.08.005

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