Prodrug-CCM

As a pioneer and undisputed global leader in antibody-drug conjugates (ADCs) engineering, Creative Biolabs is proud to introduce our professional antibody-directed enzyme prodrug therapy (ADEPT) development services. At present, we provide cephalosporin mustard (CCM) as a prodrug for the antibody-β-lactamase conjugate-based ADEPT development with our diverse technologies.

CCM

7-(4-carboxybutanamido) cephalosporin mustard (CCM), which could be activated in a site-specific manner by monoclonal antibody-β-lactamases conjugates targeted to antigens that locate on tumor cell surfaces, has been developed as a prodrug to treat some tumor diseases. The β-lactamases enzyme from Bacillus cereus (BCβL) or Escherichia coli (ECβL) can catalyze CCM to release the phenylenediamine mustard (PDM) via a fragmentation reaction which occurs after the β-lactam ring of CM is hydrolyzed. In vivo experiments in nude mice suggested that CCM was less toxic than 7-(Pheny1acetamido) cephalosporin mustard (CM) and PDM. Although PDM is more cytotoxic than CCM to tumor cells, treatment of the cell with L6-BCβL followed by CCM resulted in a high level of antitumor effect, which was comparable to that of PDM. Thus, CCM is a potential prodrug which can be activated with immunological specificity by a monoclonal antibody-β-lactamase conjugate.

MOA of CCM

CCM can be catalyzed by β-lactamases and thus yields high cytotoxic drug phenylenediamine mustard (PDM). N, N-Di(2-chloroethyl)-4-phenylenediamine mustard (PDM) is an alkylating antitumour agent with high cytotoxicity. Due to the production of an aziridium ion, it is highly reactive against nucleophiles. The biological activity of PDM is a result of the crosslinking of DNA in the nucleus of the cell, inducing the death of tumor cells.

Mechanism of drug release catalyzed by β-lactamase. Fig.1 Mechanism of drug release catalyzed by β-lactamase. (Vrudhula, 1993)

CCM-based ADEPT

7-(4-carboxybutanamido) cephalosporin mustard (CCM) has been used as a prodrug in an ADEPT. The L49 (IgG1) monoclonal antibody could specifically bind to p97 (melanotransferrin) that is expressed on human melanomas and carcinomas. In ADEPT system, the recombinant fusion protein L49-sFv-bL which consists of L49 antibody and Enterobacter cloacae r2-1 β-lactamase (bL) is expressed and purified in an Escherichia coli soluble expression system. L49-sFv-bL maintained the antigen binding capability of monovalent L49 as well as the enzymatic activity of βL. In vitro experiments showed that L49-sFv-bL bound to 3677 melanoma cells expressing the p97 antigen and effected the activation of CCM prodrug. After injection of L49-sFvbL into nude mice with subcutaneous 3677 tumors, results indicated that the L49-Fab’-bL conjugate yielded a much lower tumor to blood ratio (5.6 at 72 h post administration) than L49-sFv-bL. In addition, therapy experiments established that well-tolerated doses of L49-sFv-bL/CCM combinations resulted in cures of 3677 tumors in nude mice. Therefore, L49-sFv-bL appears to have promising characteristics for site-selective anticancer prodrug activation in ADEPT therapy.

Targeted cancer therapy using ADEPT. Fig.2 Targeted cancer therapy using ADEPT. (Napp, 2016)

As your scientific partner, Creative Biolabs can assist in the design of prodrug for application in ADEPT development. We provide high-quality CCM synthesis service for the antibody-β-lactamase conjugate-based ADEPT development. If you are interested in our products and services associated with ADEPT, please contact us for more information and a detailed quote.

References

  1. Vrudhula, V. M.; et al. Antitumor activities of a cephalosporin prodrug in combination with monoclonal antibody-beta-lactamase conjugates. Bioconjugate chemistry. 1993, 4(5), 334-340.
  2. Napp. J.; et al. In vivo imaging of tumour xenografts with an antibody targeting the potassium channel Kv10.1. Eur Biophys J. 2016, 45(7), 721-733.

For Research Use Only. NOT FOR CLINICAL USE.


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