Podocalyxin and TRA-related antibody, methods of preparation and uses as an anti-cancer therapeutic agent
Inventors
SCHOPPERLE, WILLIAM MICHAEL • Tan, Edwin Saavedra • JU, YAWEN • HOLMQVIST, MATS HARALD • TAK, YOUNGBIN • HOLMQVIST, AN MARY
Assignees
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Publication Number
US-10509038-B2
Publication Date
2019-12-17
Expiration Date
Abstract
The invention relates to an antibody or an antigen-binding fragment thereof, including a heavy chain and a light chain, with heavy chain complementarity determining regions 1 to 3 having the amino acid sequences of SEQ ID NOS. 1 to 3, respectively, and light chain complementarity determining regions 1 to 3 having the amino acid sequences of SEQ ID NOS. 4 to 6, respectively. In addition, the invention relates to an anti-cancer therapeutic agent including the antibody or the antigen-binding fragment thereof.
Core Innovation
The invention relates to a monoclonal antibody consisting of a heavy chain having the amino acid sequences of SEQ ID NOS. 1 to 3 and a light chain having the amino acid sequences of SEQ ID NOS. 4 to 6. The antibody is monoclonal antibody CM-918 (Bstrongomab-9A) and targets the embryonic/pluripotent Podocalyxin TRA-epitope (TRA-Podocalyxin).
The described binding is expected to selectively bind embryonic stem and pluripotent embryonal carcinoma cells while sparing differentiated cells. The antibody is discussed in the context of targeting TRA-Podocalyxin (PODXL) associated with TRA carbohydrate epitope (TRA-1-60, TRA-1-81).
Antibody binding specificity is supported by Western blot showing a binding band in the range of about 200 to 240 kDa in TRA-Podocalyxin+ pluripotent cells and not in TRA− controls. Overlap of fluorescence staining is described with anti-TRA-1-60 staining.
Therapeutic use is described as an anti-cancer agent, including antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-drug conjugate (ADC) approaches. Experimental support is included for CM-918-vc-MMAE ADC and related constructs, with reported in vitro potency against TRA-Podocalyxin+ targets and described in vivo xenograft tumor regression.
Claims Coverage
The partial content includes one independent claim (clm-00001). It provides one central inventive definition based on specific heavy-chain and light-chain amino acid sequence sets.
Monoclonal antibody defined by specific heavy-chain and light-chain sequences
A monoclonal antibody consisting of a heavy chain having the amino acid sequences of SEQ ID NOS. 1 to 3 and a light chain having the amino acid sequences of SEQ ID NOS. 4 to 6.
Independent claim coverage is limited to the sequence-defined monoclonal antibody specified by SEQ ID NOS. 1–3 for the heavy chain and SEQ ID NOS. 4–6 for the light chain.
Stated Advantages
Selectively binds embryonic stem/pluripotent embryonal carcinoma cells while sparing differentiated cells.
Immunohistochemistry shows strong membrane staining in multiple cancers with limited normal tissue staining.
Reported ADCC/CDC cytotoxicity against TRA-Podocalyxin+ targets.
Reported in vitro potency of CM-918-vc-MMAE ADC against TRA-Podocalyxin+ targets.
Reported in vivo xenograft tumor regression using CM-919-vc-MMAE ADC.
Documented Applications
Anti-cancer therapeutic use as an agent engaging ADCC and CDC and as an antibody-drug conjugate approach (e.g., CM-918-vc-MMAE ADC and CM-919-vc-MMAE ADC).
Immunohistochemistry-described targeting of cancers including oral, ovarian, prostate, breast, pancreatic, colon, gastric, and esophageal cancers.
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