Antibody targeting of ADAM8 for treatment of triple-negative breast cancer

Triple negative breast cancersTNBCsaccount forof breast cancer deaths and lack targeted therapiesWe identified the non essentialcell surface protein ADAMas an important target on TNBCADAMis present inof primary TNBCsandof all breast cancer patient derived metastasesbut absent in normal breast tissuesHigh ADAMmRNA levels correlate with poor patient outcomeThe ADAMMetalloproteinaseMPand DisintegrinDIdomains drive tumor growth and metastasis through release of pro angiogenic factors and activation ofintegrin on cancer cellsrespectivelyA research only anti ADAMmouse monoclonal antibodymAbthat inhibits the MP and DI domains decreased TNBC tumor growth and metastasisvalidating ADAMas a therapeutic targetA PCT patent applicationUSwas filed Mayby DrsSonensheinMineva and Romagnoliand Tufts Universitywith claims to target the ADAMMPDI domainsdual antagonist antibodyfor treatment of breast and other ADAMdriven cancerse ggastriclungpancreaticIn OctoberAdecto PharmaceuticalsIncAPwas founded by theinventors to develop ADAMantibody based therapies for aggressive cancersSuccessful completion of the aims of our Phase I STTR has led toigeneration of anti human ADAMmouse mAbstermed ADPsthat inhibit both the MP and DI domainsand iiidentification of two lead candidatesADPADPthat decrease growth and dissemination of TNBC cell line derivedCLDtumors and improve mouse survivalWe propose ADAMdual antagonist antibody therapy will become a new component of TNBC careThrough discussions with oncologistswe identified recurrent brain metastasis free TNBC as our first indication and a combination of humanized ADPhADPStandard of CareSoCchemotherapyCTas the treatment regimenPreliminary results with ADPNab PaclitaxelN PACdemonstrate robust reduction in tumor regrowth compared to NPAC alone in support of this approachImmunohistochemistry ofnormal human tissues detected ADAMprimarily in gastrointestinal neuroendocrine cellsNECsand occasionally in stomach and lung inflammatory immune cellsThis limited expression pattern suggests targeting ADAMcarries a low risk of side effectsOuraims are toIdentify the most effective SoC CTe gN PAC CisplatinADP combination using CLD and patient derived xenograft modelsGenerate humanizedhADPhADPvariants by CDR graftingidentify a functional lead for each in cell based assays and confirm activity in humanized micePerform early safety studiesdetermine effects of ADAMinhibition on primary PBMCs and NECsconfirm hADP lack of immunogenicity andamptissue cross reactivityThese studies will identify a lead hADP with early safety data and an entry path to the clinicGuidance from GLP andampGMP consultants will ensure AP is ready to transition to IND studies and allow us to attract investors strategic partners and Phaseb funding for continued development and commercialization of a novel treatment for TNBC patientswho currently lack targeted therapies We have identified a protein called ADAMon the surface of Triple Negative Breast CancerTNBCtumorswhich lack targeted therapies and account for more thanof thebreast cancer deaths yearly worldwideand validated it as a target for treatmentAs proposed in our Phase I STTR grantwe successfully isolated and characterized highly specific inhibitory mouse monoclonal anti ADAMantibodiestermed ADPsand identified the top two inhibitors which reduced TNBC tumor growth and spread in mice and improved overall survivalIn this Phase II SBIR grantaims are proposed to identify a first line chemotherapy that works more effectively in combination with an ADPhumanize our top two antibodiesand perform early safety studies to allow us to select a lead for further development and entry into the clinicwhich could revolutionize treatment of TNBC by providing a more effective intervention that improves survival of patients with these very aggressive tumors