Efficient inhibition of B-cell lymphoma xenografts with a novel recombinant fusion protein: anti-CD20Fab-LDM.
Lidamycin (LDM) is a new member of enediyne antitumor antibiotics family that can be separated and reconstituted. It consists of a labile active enediyne chromophore (AE) and a noncovalently bound apoprotein (LDP). LDM is now in phase II clinical trials. In this study, we described the antitumor features of a fusion protein of LDM, anti-CD20Fab-LDM, targeted to CD20 expressed by B-lymphoid malignancies. Especially, LDM was prepared by a novel two-step method including DNA recombination and molecular reconstitution. Anti-CD20Fab-LDM exerted potent cytotoxicity against CD20+ B-cell lymphoma cell lines in vitro (IC50: 10-30 pM) and in the Raji xenograft model. Two Raji xenografts were allowed to grow to an initial mass of 80 and 500 mm³, respectively, and then anti-CD20Fab-LDM was administered intravenously with the highest dose of 4 nmol kg⁻¹ . The inhibition rates of tumor growth were 90.1 and 85%, which were saliently superior to those of nontargeted LDM. It is noteworthy that anti-CD20Fab-LDM can inhibit the growth of patient-derived cells, including rituximab-resistant patient-derived cells. Thus, CD20-targeted delivery of LDM is a specific and potent therapeutic strategy for B-lymphoid malignancies. In addition, the two-step approach could serve as a new technology platform for making a series of highly potent engineered antibody-based drugs.
Xin
C
C
State Key Laboratory of Experimental Hematology, Department of Pharmacy, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, PRC.
Ye
S
S
Ming
Y
Y
Shenghua
Z
Z
Qingfang
M
M
Hongxing
G
G
Xu
S
S
Yuanfu
X
X
Yuan
Z
Z
Dongmei
F
F
Juanni
L
L
Yingdai
G
G
Lianfang
J
J
Rongguang
S
S
Zhenping
Z
Z
Jianxiang
W
W
Tao
C
C
Chunzheng
Y
Y
Dongsheng
X
X
Yongsu
Z
Z
D000617:Aminoglycosides / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D053281:Enediynes / Q000737:chemistry / Q000627:therapeutic use; D005260:Female; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
D000617:Aminoglycosides; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D053281:Enediynes; D011993:Recombinant Fusion Proteins; C555620:anti-CD20Fab-LDM protein; C058024:C 1027