New modular delivery system for diagnostic and therapeutic pre-targeting using tautomer-specific monoclonal antibody EM-6-47 and 3-substituted adenines
✍ Scribed by Kai Krüger; Christoph Jochum; Karl-Heinz Glüsenkamp; Christa Krüsemann; Petra Lorenz; Gertrud Eberle-Adamkiewicz; Wolfgang Drosdziok; Dietrich W. Beelen; Heinz H. Coenen; Manfred F. Rajewsky
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- French
- Weight
- 267 KB
- Volume
- 77
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
We have developed a new modular affinity system for the 2-step delivery of functional molecules to target cells. The system is based on the tautomer-specific monoclonal antibody (MAb) EM-6-47, which binds to 3-and 3,8-substituted adenines with high affinity (K a G 10 9 l/mol) without crossreacting with naturally occurring purine derivatives. This MAb serves as the hapten-specific fusion partner to produce bispecific MAbs (bs-MAbs) recognizing a target cell antigen and a low-m.w. hapten as carrier molecule for, e.g., radionuclides. Either the C-8 or the N-3 position of adenines can be used for conjugation with effector molecules; the remaining position may be substituted with different moieties to modulate the pharmacokinetics of the haptens. Different 3-and 3,8-substituted adenines conjugated to the chelates DOTA and DTPA or to the drug daunomycin were synthesized. Adenine-chelate derivatives were efficiently labeled with 111 In and 90 Y, while high-affinity binding of 3-substituted adenines to MAb EM-6-47 remained almost unaffected by the conjugation to radiochelates. To confirm the validity of the delivery system, a prototype bs-MAb, EM-168-47, was generated by somatic cell fusion of MAb EM-6-47 and MAb EM-168-2, the latter recognizing a surface antigen on canine hematopoietic cells. Two-step targeting assays in vitro verified the bs-MAbmediated, dose-dependent delivery of 111 In-labeled adeninechelate derivatives to myeloid cells. This system represents a powerful tool for new pre-targeting approaches relying on bs-MAbs and low-m.w. haptens. Suitable cellular antigens can be targeted by fusing the appropriate MAbs with haptenspecific MAb EM-6-47, and tailor-made 3-substituted adenines may be labeled with diagnostic or therapeutic radionuclides, cytotoxic drugs or other functional molecules. Int.