Chemically programmed monoclonal antibodies for cancer therapy: Adaptor immunotherapy based on a covalent antibody catalyst

Abstract

Proposing that a blend of the chemical diversity of small synthetic molecules with the immunological characteristics of the antibody molecule will lead to therapeutic agents with superior properties, we here present a device that equips small synthetic molecules with both effector function and long serum half-life of a generic antibody molecule. As a prototype, we developed a targeting device that is based on the formation of a covalent bond of defined stoichiometry between a 1,3-diketone derivative of an integrin ␣v␤3 and ␣v␤5 targeting Arg-Gly-Asp peptidomimetic and the reactive lysine of aldolase antibody 38C2. The resulting complex was shown to (i) spontaneously assemble in vitro and in vivo, (ii) selectively retarget antibody 38C2 to the surface of cells expressing integrins ␣v␤3 and ␣v␤5, (iii) dramatically increase the circulatory half-life of the Arg-Gly-Asp peptidomimetic, and (iv) effectively reduce tumor growth in animal models of human Kaposi's sarcoma and colon cancer. This immunotherapeutic has the potential to target a variety of human cancers, acting on both the vasculature that supports tumor growth as well as the tumor cells themselves. Further, by use of a generic antibody molecule that forms a covalent bond with a 1,3-diketone functionality, essentially any compound can be turned into an immunotherapeutic agent thereby not only increasing the diversity space that can be accessed but also multiplying the therapeutic effect.

Small molecule drug activity in melanoma models may be dramatically enhanced with an antibody effector

“…In the same study, CNTO95 displayed potent antiangiogenic effects in both rodent model and novel nonhuman primate model in cynomolgus monkeys. 28 In the study by Rader et al, 32 we showed that cp38C2 could inhibit tumor growth through an antiangiogenic effect. In that study, a v b 3 /a v b 5 -negative human colon carcinoma cells SW1222 were injected into nude mice.…”

“…32 Briefly, 96-well plates were precoated with 50 lL of 2 lg/mL vitronectin, fibrinogen or HIV-1 tat protein overnight at 4°C, washed twice with 100 lL HBSS and blocked with 100 lL cell culture media for 30 min at 37°C. To examine monolayer cell growth, a total of 2.5 3 10 3 (HUVEC), 2.5 3 10 3 (MAEC), 1 3 10 3 (MS1), 1 3 10 3 (M21) or 1 3 10 3 (M21L) cells were plated, treated with the indicated concentrations of SCS-873 or cp38C2, ranging from 0.01 to 100 lM (from 0.005 to 5 lM for cp38C2), and incubated at 37°C for 64 hr in a humidified CO 2 incubator.…”

“…The synthesis of b-diketone (JW) conjugated to BSA (JW-BSA), SCS-397 and SCS-873 were previously described. 32,34 Chemical programming A stock solution of 10 mg/mL (66.6 lM) 38C2 IgG in PBS (pH 7.4), stored at 4°C, was used. Stock solution of 8.73 mg/mL (10 mM) SCS-873 in 100% ethanol, stored at 280°C, was used.…”

“…30,31 We have developed a chemically programmed antibody approach that is unique, wherein small synthetic molecules and catalytic mAb form a reversible covalent bond that results in the reprogramming of the specificity of the antibody both in vitro and in vivo. 32 The chemically programmed antibody (cp38C2) is prepared by covalently linking a small synthetic molecule, RGD mimetic SCS-873, which binds specifically to integrins a v b 3 and a v b 5 , to aldolase mAb 38C2 (Fig. 1).…”

Breaking the one antibody–one target axiom

“…The resulting conjugate of small molecule and antibody is a cpAb. Significantly, we have demonstrated that chemical programming of a catalytic antibody can occur both in vitro and in vivo to have a therapeutic effect in disease models (3,5). Key to this approach is the development of catalytic antibodies that operate using covalent reaction mechanisms (6, 7).…”