Dose-Dependent Induction of an Idiotypic Cascade by Anti-Glycosaminoglycan Monoclonal Antibody in apoE−/− Mice: Association with Atheroprotection

Abstract

Atherosclerosis, the underlying pathology of most cardiovascular diseases, is triggered by the retention of apolipoprotein B (apoB)-containing lipoproteins in the arterial wall through electrostatic interactions with glycosaminoglycan (GAG) side chains of proteoglycans. Previously, we reported the antiatherogenic properties of the chimeric monoclonal antibody (mAb) chP3R99-LALA, which binds sulfated GAGs, inhibits low-density lipoprotein (LDL)–chondroitin sulfate (CS) association, and abrogates LDL oxidation and foam cell formation. In preventive and therapeutic settings, apoE-deficient (apoE−/−) mice immunized with 50 μg of this mAb showed reduced atherosclerotic lesions related with the induction of autologous anti-GAG antibodies. Knowing that age and sex are major non-modifiable risk factors in the development of atherosclerosis, the present study aimed to assess the influence of these variables on the capacity of chP3R99-LALA mAb to generate an anti-CS antibody response. Also, we aimed at defining the impact of the dose of chP3R99-LALA on the anti-CS antibody induction and the atheroprotective effect of this mAb in apoE−/− mice. Neither age nor sex had an impact in the IgG anti-CS antibody response induced by s.c. immunization with this mAb. Moreover, chP3R99-LALA mAb reduced atherosclerotic lesions to a similar extent in both young male and female apoE−/− mice fed a hypercholesterolemic diet and, in middle-aged female apoE−/− mice, with spontaneous lesions. On the other hand, increasing the dose of chP3R99-LALA (200 vs. 50 μg) elicited an anti-idiotype antibody cascade characterized by higher levels of anti-idiotype (Ab2), anti-anti-idiotype (Ab3), and anti-CS antibody responses. Moreover, this dose increment resulted in a striking reduction of aortic atherosclerotic lesions in immunized mice.

Phase I trial of anti-GD2 monoclonal antibody hu3F8 plus GM-CSF: Impact of body weight, immunogenicity and anti-GD2 response on pharmacokinetics and survival

“…28 In a rabbit and an apoE ¡/¡ mouse model, an affinity enhanced P3 antibody with the ability to inhibit LDL-chondrotin sulfate association, induced an active anti-chondroitin sulfate antibody response, preventing the formation of, and arresting the progression of atherosclerosis. [29][30][31] In our patients, the ability to mount a spontaneous anti-GD2 response was negatively influenced by the HAHA response but not by hu3F8 dosage level. Patients with positive HAHA (resulting in fewer treatment cycles received) had anti-GD2 response below the median.…”

Smooth Muscle Cell-Proteoglycan-Lipoprotein Interactions as Drivers of Atherosclerosis

“…Further research using chP3R99 in the same mouse model established the chP3R99-LALA variant restricted the progression of atherosclerosis in apoE À/À mice by preventing initial CS-LDL complex formation (Delgado-Roche et al 2015). Both the efficiency of the chP3R99-LALA mAb in initiating the anti-idiotype cascade and anti-atherogenic benefits were dose-dependent in apoE À/À mice but were independent of the sex and age of the mice (Sarduy et al 2017). The mAb was also shown to decrease inflammation and halt lesion development of advanced stages of atherosclerosis in male apoE À/À mice (Brito et al 2017).…”

Monoclonal antibody chP3R99 reduces subendothelial retention of atherogenic lipoproteins in Insulin-Resistant rats:Acute treatment versus long-term protection as an idiotypic vaccine for atherosclerosis

“…The chP3R99 mAb and the control hR3 continue to be generated at the CIM (54, 55). It has previously been reported that chP3R99 has the capacity to interfere with the development and progression of atherosclerosis in mice and rabbit models (37–39, 46). In an extension to this work, we now demonstrate that chP3R99 can interfere with the interaction of both LDL and RM lipoproteins to vascular regions susceptible to atherogenesis in a rat model of IR.…”