Recently, Northeast Pharmaceutical disclosed that in order to accelerate the advancement of its collaboration with the United StatesMedAbomecompanyADCMedications andCAR-TThe subsidiary established through the implementation of the cell therapy technology cooperation project has completed its industrial and commercial registration. Northeast Pharmaceutical stated that innovative drug research and development is characterized by high technology, high risk, and high added value. Whether the products can successfully be commercialized in the future is susceptible to the influence of some uncertain factors.
In the past two years,ADCThe number of followers has increased significantly.ADCWhat are the advantages of the drug? (Target, technological advantages, etc.) Why is there a willingness to develop and invest in it?ADCTrack investment? In R&D,ADCWhat is the research and development difficulty level, where are the barriers, and what is the capital investment like? CurrentlyADCWhat stage of development is it in? What is the progress of domestic R&D? Frost & SullivanFrost & SullivanJiang Tengfei, Consulting Director for Healthcare in Greater China at Frost & Sullivan (hereinafter referred to as 'Frost & Sullivan'), was interviewed by 'Economic Times'. Interview, to jointly discuss the aforementioned topics.
Economic Times
Q
In the past two years,ADCThe number of followers has increased sharply, in your viewADCWhat are the advantages of the drug? (Target, technological advantages, etc.) Why is there a willingness to develop and invest in it?ADCTrack investment?
Jiang Tengfei
Frost & Sullivan's Healthcare Industry Consulting Director for Greater China
ADCTechnology is throughlinkerLinking antibodies (with strong specificity) with small molecule cytotoxic drugs (with strong lethality), utilizing the specificity of antibodies to target and transport small molecule cytotoxic drugs to targeted tissues/The parts play their roles.
ADCDrugs can reduce the systemic toxic and side effects of small molecule cytotoxic drugs, increase the therapeutic window, and expand bystander killing effects. withDS-8201For example, the antibody isHER2The targeted trastuzumab can accurately identifyHER2Cancer cells with positive expression; Small molecule cytotoxic drugs are camptothecin derivativesDxd), has strong membrane permeability, and can targetHER2positive/Kills cancer cells with negative expression; its tetrapeptide linker, possesses1:8The drug antibody ratio is such that each antibody can carry more small molecule cytotoxic drugs.
ADCThe clinical advantages of the drug mainly lie in its clinical efficacy in the field of anti-tumor therapy (for example: breast cancer, urothelial carcinoma, gastric cancer, etc.).DS-8201For example,DESTINY-Breast03The findings have promptedESMOGuidelines for the Diagnosis and Treatment of Advanced Breast Cancer, No.6International Consensus on Advanced Breast Cancer (ABC6),2022yearV2versionNCCNBreast cancer guidelines recommendDS-8201asHER2Preferred regimen for second-line treatment of advanced positive breast cancer.
andDESTINY-Breast04is targeted atHER2Low-expression patientsIIIPhase I clinical trials, and stunning results were obtained,HRpositive,HER2Among patients with low expression,DS-8201Compared with chemotherapy chosen by doctors, it reduces the risk of disease progression or death in patients49%,DS-8201Median progression-free survival in the groupPFS) for10.1months, chemotherapy group was5.4months. Compared with chemotherapy,HRAmong the positive patient group,DS-8201Reduce the risk of death36%Meanwhile,DS-8201Median survival time in the groupOperating System) for23.9months, chemotherapy group was17.5months; this milestone breakthrough meansDS8201or will be used for those who originally lacked targeted therapyHR+/HER2-Treatment options are provided for breast cancer patients.
Q
In R&D,ADCWhat is the research and development difficulty, what are the barriers, and how is the capital investment structured?
Jiang Tengfei
Frost & Sullivan Greater China Healthcare Industry Consulting Director
target,linkerantibodypayloadsyesADCsFour core R&D priorities of the drug. The highest barrier lies in the development of targetslinkerChoice.
target Ideal targets are those that are highly expressed on the surface of tumor cells, lowly or not expressed in normal tissues, or are limited to specific tissues. Targets expressed in normal tissues can easily lead to 'off-target' effects and also reduce the enrichment of cancer tissues.ADCdose, reduceADCDrug therapeutic window. Leukocyte surface differentiation antigens are the most widely used.ADCTargets, as these antigens are highly expressed in tumor tissues but not in normal hematopoietic tissues/Low expression, more than 20 of which are currently in clinical developmentADCHalf of the drug targets are leukocyte surface antigensCD19,CD22,CD30,CD33,CD56,CD74,CD79b,CD138(evening).
linkerIn terms of research and development, Mainly divided into cuttable and non-cuttablelinkerDesignable for cuttinglinkerIt mainly utilizes the environmental differences between the blood system and tumor cells, hence cleavage after environmental transformationlinkerEfficiency is crucial. For example, proteases are sensitive tolinkerIt is stable in blood, but it is cleaved and released as active toxins in lysosomes rich with proteases that recognize its specific protein sequence. It is not cleavable.linkerConsisting of stable bonds resistant to proteolytic degradation, its stability in blood is crucial. It can only be released by lysosomes and proteases after entering the cell, where it can be associated with amino acid residues derived from antibody degradation.payloadTo kill cancer cells. In addition,linkerThe choice of targets is also closely related.
In terms of production, traditionallinkerTechnology generally involves reducing disulfide bonds between antibody chains,payloadsCoupled to cysteine or lysine. Lysine coupling results in each antibody being coupled0 - 8A drug molecule, the conjugation site generally occurs at approximately20A lysine residue, therefore, the coupling method will produce millions of different formsADCDrug molecules. Diverse heterogeneity of conjugation at different sitesADCin vivoPKThe dynamic properties are also different, and the difficulty of industrial production in the later stages will increase. In terms of production, sample consistency between batches is a core barrier.
antibody: High specificity is at the core, and currently, mostADCAntibodies are allIgG1It has relatively strong antibody-dependent cytotoxicityADCCcomplement-dependent cytotoxicityCDC), with a long half-life, andIgG1The hinge formed within the cell is easy to restore and produce. Compared to othersIgG2andIgG4In comparison,IgG1andIgG3ofADCCandCDCSignificantly stronger;IgG1thanIgG3The half-life is longer, allowing for sustained lethality at the tumor site. At the same time, to reduce immunogenic issues,ADCAntibodies are all engineered using humanized or fully human technologies.
Toxin moleculepayload): Currently, the toxic molecules under development mainly include microtubule inhibitors andDNADamage agents, focusing on factors such as conjugate stability and hydrophobicity, as well as how to combine with antibodies to achieve greaterpayloadThe load capacity is also a core R&D issue.
ADCThe R&D barrier is relatively high, and for a single first-in-class innovative drugFirst in classThe complete project cycle is in7 - 8In [year], the investment amount was in10Over USD100 million, targeting existing targetsADCDevelopment (e.g., optimizationlinkerOptimizing small molecule cytotoxic drugs or antibodies can significantly reduce time consumption and costs.
Q
currentlyADCWhat stage is it in of development? What is the progress of R&D domestically?
Jiang Tengfei
Frost & Sullivan Greater China Healthcare Industry Consulting Director
First generationADCMedication:2000Year USAFDAApproved the firstADCDrug launchGemtuzumab ozogamicin(commodity nameMylotarg, Wyeth (a subsidiary of Pfizer), targetingCD33However, compared to other anti-cancer drugsGemtuzumab ozogamicinThere are no significant clinical advantages, and it has severe hepatotoxicity.2010year,Gemtuzumab OzogamicinTake the initiative to withdraw from the market.
Second GenerationADCThe drug is better than the first generationCMCFeatures. Second generationADCDrug representatives includeBrentuximab vedotin（2011year8monthFDAlistedAdo-trastuzumab emtansine injection（2013year2monthFDAlistedInotuzumab Ozogamicin（2017year8monthFDAlisted). However, the second generationADCThe drug treatment window is short, with low tolerance, high plasma clearance efficiency, and low in vivo efficacy.
third generationADCDrugs bind site-specifically, significantly optimizing antibodies andlinkerThe representative drugs arePolatuzumab vedotin,Enfortumab vedotin,Fam-trastuzumab deruxtecanDevelopingDARvalue2or4Antibody conjugates significantly improve the stability and pharmacokinetics of drugs, increasing drug activity and binding to cells with lower antigen levels.
2020year1monthT-DM1in ChinaNMPAApproved for marketing, followed by Takeda's Vebrutuximab2020year5Monthly) and Rongchang Biologics' vedolizumabRC48)2021year6Month) in ChinaNMPAListing, this3A landmark event represents the Chinese marketADCThe drug began to make a name for itself. And AstraZeneca&The breakthrough drug jointly developed by the First Sanofi & Daiichi Sankyo Group - Dostarcept (DS8201) is also2022year4The moon is in ChinaNMPAPriority approval is granted, expected to be available in2023yearH1Approved for marketing, currently in clinical trials in ChinaADCdrug exceeds60One, which will also continue to receive attention in the future.
*This interview was published in "Economic Times", with reporter Zhang Yuguqi as the lead contributor, and the original title was "The The sales of star anti-cancer drugs have slowed down, and Rongchang Biotech suffered a huge loss in its first year of listing.10hundred million,ADC"The recovery" is long >> (Click on "Read the Original Article" at the end of the text to read the full report).
