Anti-TIM-1-vcMMAE | CDX-014 (Drug Description)

The anti-TIM-1-vcMMAE CDX-014 is an investigational antibody-drug conjugate being developed by Celldex Therapeutics, is designed to target the extracellular domain of the T cell immunoglobulin mucin domain 1 (TIM-1),  a type I transmembrane protein that was originally described as kidney injury molecule 1 (KIM-1) due to its elevated expression in kidney and urine after renal injury.

Tim-1 expression is also upregulated in several human cancers, most notably in renal cell carcinoma (RCC) and ovarian carcinomas, but has very restricted (limited) expression in healthy tissues thus representing a promising target for antibody mediated therapy.

TIM-1 is expressed in 70-90% of RCC tumor samples, associated with advanced RCC.

Novel ADC
Researchers at Celldex Therapeutics have developed a fully human monoclonal IgG1 antibody specific for extracellular domain of TIM-1. This antibody was shown to bind purified recombinant chimeric TIM-1-Fc protein and TIM-1 expressed on a variety of transformed cell lines, including Caki-1 (human renal clear cell carcinoma), IGROV-1 (human ovarian adenocarcinoma) and ACHN (human renal cell adenocarcinoma).

Internalization studies using confocal microscopy revealed the antibody was rapidly internalized by cells in vitro. 

Antibody-drug Conjugate
An antibody-drug conjugate (ADC) was produced with the anti-TIM-1 antibody covalently linked via via a valine-citrulline (vc) peptide linker, to a potent cytotoxin, monomethyl auristatin E (MMAE) using Seattle Genetics’ proprietary technology and designated as CDX-014. This novel, investigational, drug  was shown to exhibit in vitro cytostatic or cytotoxic activity against a variety of TIM-1 expressing cell lines, but not on TIM-1 negative cell lines.

Using the Caki-1 and IGROV-1 xenograft models, CDX-014 showed significant anti-tumor activity in the range of 75-300 μg/dose given every four days for a total of four doses. Activities are on-going to support the manufacturing and IND-enabling studies in order to advance CDX-014 towards clinical studies in renal cell carcinomas and potentially other TIM-1 expressing tumors

Upon administration of Anti-TIM-1-vcMMAE CDX-014, the monoclonal antibody moiety targets and binds to TIM-1. Upon internalization and proteolytic cleavage, monomethyl auristatin E (MMAE) is released into the cytosol of TIM-1-expressing tumor cells, binds to tubulin and inhibits its polymerization, resulting in G2/M phase arrest and tumor cell apoptosis.

Clinical trials status

Drug Candidate and Indication
CDX-014

Advanced/metastatic clear cell or papillary renal cell carcinoma


Additional data: 
Originator

 

Amgen and CuraGen

 

Latest development stage

 

Phase I/II

 

Synonyms
ADC anti-TIM-1-vcMMAE
CDX-014
ADC CDX-014
Antibody-drug conjugate CDX-014
CR014-vcMMAE
CR014-vc-MMAE

Reference:
[1] Thomas LJ, Vitale L, O’Neill T, Dolnick R, Wallace PK, Minderman H, Gergel LE, Forsberg EM, Boyer JM, et al. Development of an antibody-drug conjugate targeting TIM-1 for the treatment of ovarian and renal cell carcinoma. AACR 2014 (Monday, Apr 07, 2014, 1:00 PM – 5:00 PM) Hall A-E, Poster Section 31; Poster Board Number 10.

[2] Thomas LJ, Vitale L, O’Neill T, Dolnick RY, Wallace PK, Minderman H, Gergel LE. et al. Development of a Novel Antibody-Drug Conjugate for the Potential Treatment of Ovarian, Lung, and Renal Cell Carcinoma Expressing TIM-1. Mol Cancer Ther. 2016 Dec;15(12):2946-2954. Epub 2016 Sep 26. [Full article]