Antibody-decorated Polymersomal Mertansine Conjugates For Targeted Depletion Of Orthotopic Multiple Myeloma

Multiple myeloma(MM),as the second ranking hematological malignancy,tends to become relapsed and drug-resistant and is a currently incurable with high fatality.The recent approval of two CD38-targeted monoclonal antibodies and one BCMA-targeted antibody drug conjugate(ADC)has provided new treatment options for MM patients,yielding improved treatment outcomes.However,antibody and ADCs typically need large amount of antibody and high cost.Furthermore,antibodies that used generally in combination with small molecular drugs remain suffering potential side effects and drug resistance,and ADCs have a quite low drug-to-antibody ratio.To this end,monoclonal antibody decorated polymersomal mertansine conjugates were engineered for CD38 and BCMA-targeted chemotherapy and depletion of orthotopic MM in vivo.In Chapter 1,the status quo,clinical diagnostic methods and treatment regimens of MM were briefly introduced.Antibodies,ADCs and actively targeted nanomedicines used for MM therapy were summarized as well.In Chapter 2,daratumumab-directed polymersomal mertansine conjugates(Dar-IPs-DM1)were developed for safe and CD38-targeted chemotherapy,thus depleting orthotopic MM in vivo.Dar-IPs-DM1 was prepared via co-assembly of N3-PEG-P(TMC-DTC)and PEG-P(TMC-DTC)with simultaneous disulfide-crosslinking and DM1 conjugation,followed by facile click reaction with Dar.Dar-IPs-DM1 with tailored antibody density and simple fabrication procedure possessed high drug-to-antibody ratio,stable DM1 conjugation and reduction-responsive DM1 release.Dar6.2-IPs-DM1 with the best targetability induced potent anti-MM activity in CD38-overexpressed LP-1 MM cells with an IC50 of 2.7 ng/mL,3.9-fold lower than non-targeted Ps-DM1,while showing negligible toxicity to normal cells.Interestingly,orthotopic LP-1-Luc MM bearing mice following treatment with Dar6.2-IPs-DM1 exhibited complete depletion of LP-1-Luc cells,relieved osteolysis and significantly prolonged median survival time from 35 d(PBS group)to 124 d.Unlike CD38 with certain expression on normal tissues,BCMA is specifically expressed on MM cells and mature B lymphocytes,while basically undetectable in normal tissues and cells.In Chapter 3,Anti-BCMA antibody and single chain variable fragment(Anti-BCMAscFv)modified polymersomal mertansine conjugates were constructed similarly as Dar-IPs-DM1,their in vitro targetability and anti-MM activity were investigated and compared.Thereinto,Anti-BCMAscFv was clicked onto the surface of Ps-DM1 via site-specific modification from its C-end thiol group.Anti-BCMA5.5-IPs-DM1 and Anti-BCMAScFv5.1-IPs-DM1 showed similar targetability to BCMA-overexpressed LP-1 MM cells,inducing high anti-MM activity with IC50 values of 3.5 and 3.4 ng/mL,respectively,comparable to Dar-IPs-DM1 in LP-1 cells.However,in BCMA-negative CCRF cells,cell viability was over 40%even at a DM1 concentration as high as 500 ng/mL.In Chapter 4,a summary of the thesis and prospect of future works were provided.