IMC-A12, a Human IgG1 Monoclonal Antibody to the Insulin-Like Growth Factor I Receptor: Fig. 1.

2007 ◽  
Vol 13 (18) ◽  
pp. 5549s-5555s ◽  
Author(s):  
Eric K. Rowinsky ◽  
Hagop Youssoufian ◽  
James R. Tonra ◽  
Phillip Solomon ◽  
Douglas Burtrum ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Growth Factor ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Igg1 Monoclonal Antibody ◽  
Human Igg1 ◽  
Growth Factor I ◽  
Human Igg1 Monoclonal Antibody

A phase I, first in man study of weekly IMC-A12, a fully human insulin like growth factor-I receptor IgG1 monoclonal antibody, in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3505-3505 ◽  
Author(s):  
C. S. Higano ◽  
E. Y. Yu ◽  
S. H. Whiting ◽  
M. S. Gordon ◽  
P. LoRusso ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Growth Factor ◽  
Phase I ◽  
Solid Tumors ◽  
Human Insulin ◽  
Clinical Activity ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Igg1 Monoclonal Antibody ◽  
Growth Factor I

3505 Background: IMC-A12 is a fully human IgG1 monoclonal antibody directed against the human insulin like growth factor-I receptor. The safety and maximum tolerated dose (MTD) of IMC-A12 are being evaluated in an on-going a phase I trial. Methods: Patients (pts) with ECOG PS = 2 and advanced refractory solid tumors receive IMC-A12 weekly for 4 infusions per cycle until progression. After cycle one only, there is a two week observation period. Six cohorts of IMC-A12 are planned at 3, 6, 10, 15, 21, 27mg/kg. Sampling for PK and human anti-human antibodies directed against IMC-A12 occurs before and after the first and fourth doses of each cycle. Results: Fifteen pts have been treated, 7 at 3 mg/g, 4 at 6 mg/kg, 3 at 10 mg/kg and 1 at 15 mg/kg. Data is available for the first 11 pts: 7 male, 4 female, median age 56 years (range: 45–70). Treatment related toxicities for the first 11 pts include: grade 1 pruritis, rash, discolored feces; grade 2 anemia, psoriasis, hyperglycemia, infusion-related reaction; grade 3 hyperglycemia. Four of 11 pts have stable disease: 2 at the 3 mg/kg dose remain stable for >9 months (1 male breast cancer,1 hepatocellular cancer) and 2 at the 6 mg/kg dose (1 bladder, 1 endometrial) were stable after cycle 1. One pt with prostate cancer had >25% decline in PSA and stable radiographic disease at time of study discontinuation (week 5) for DLT. Non-compartmental PK analysis reveals a mean t1/2 of 148 and 209 hrs, mean Cmax of 333 and 415 ug/mL, and mean AUC0-Inf of 51317 and 80727 hr*ug/mL at the 3 and 6 mg/kg dose levels, respectively. Target trough levels have been achieved. Conclusions: Weekly administration of IMC-A12 appears to be well tolerated and the MTD has not been reached. The PK profile is consistent with that of other Mab’s. There is early evidence of clinical activity and correlative IGF biomarker data will be available. IMC-A12 will be further evaluated in prostate, breast, and other cancers. No significant financial relationships to disclose.

A monoclonal antibody to human insulin-like growth factor-I: characterization, use in radioimmunoassay and effect on the biological activities of the growth factor

1989 ◽  
Vol 2 (3) ◽  
pp. 201-206 ◽  
Author(s):  
D. J. Morrell ◽  
H. Dadi ◽  
J. More ◽  
A. M. Taylor ◽  
A. Dabestani ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Growth Factor ◽  
Binding Site ◽  
Biological Activities ◽  
Rabbit Antiserum ◽  
Affinity Constant ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

ABSTRACT A monoclonal antibody (BPL-M23) to insulin-like growth factor-I (IGF-I) was obtained following immunization of BALB/c mice with human IGF-I conjugated to ovalbumin. The affinity constant of BPL-M23 for IGF-I was 10·5 litres/nmol and the cross-reactivities of IGF-II, multiplication-stimulating activity III-2 and insulin were 08, 003 and less than 0·0001 % respectively. Porcine, bovine, ovine and rabbit sera, but not rat or mouse sera, showed substantial reactivity with the antibody. Comparison of radioimmunoassay analyses of 54 human serum samples from normal subjects and acromegalic and GH-deficient patients using BPL-M23 and a polyclonal rabbit antiserum (R557A) to human IGF-I showed a high correlation, indicating the usefulness of the monoclonal antibody in radioimmunoassay. Monoclonal antibody BPL-M23 was capable of abolishing the sulphation, mitogenic and insulin-like activities of IGF-I in in-vitro bioassays, suggesting that these activities may rely upon the same receptor-binding site which is near to the antibody-binding site.

scholarly journals Purified hybrid insulin/insulin-like growth factor-I receptors bind insulin-like growth factor-I, but not insulin, with high affinity

1993 ◽  
Vol 290 (2) ◽  
pp. 419-426 ◽  
Author(s):  
M A Soos ◽  
C E Field ◽  
K Siddle
Keyword(s):  
Monoclonal Antibody ◽  
Growth Factor ◽  
Insulin Receptors ◽  
Beta Subunit ◽  
Type I ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Igf Receptors ◽  
Igf I ◽  
Growth Factor I

Hybrid insulin/insulin-like growth factor-I (IGF-I) receptors have previously been described in human placenta, but it has not been possible to study their properties in the presence of classical insulin receptors and type I IGF receptors. To facilitate the purification of hybrids, we produced an anti-peptide monoclonal antibody IGFR 1-2, directed against the C-terminal peptide of the type I IGF receptor beta-subunit. The antibody bound native human and rat type I IGF receptors, and reacted specifically with the beta-subunit on immunoblots. Solubilized placental microsomal membranes were depleted of classical type I IGF receptors by incubation with an immobilized monoclonal antibody IGFR 24-55, which reacts well with type I receptors but very poorly with hybrid receptors. Residual hybrid receptors were then isolated by incubation with immobilized antibody IGFR 1-2, and recovered by elution with excess of synthetic peptide antigen. Binding properties of hybrids were compared with those of immuno-affinity-purified insulin receptors and type I IGF receptors, by using the radioligands 125I-IGF-I and 125I-insulin. Hybrids bound approx. 20 times as much 125I-IGF-I as 125I-insulin at tracer concentrations (approx. 0.1 nM). The binding of 125I-insulin, but not 125I-IGF-I, to hybrids increased after treatment with dithiothreitol to reduce disulphide bonds between the alpha-subunits. Hybrids behaved very similarly to type I receptors with respect to the inhibition of 125I-IGF-I binding by unlabelled IGF-I and insulin. By contrast, the affinity of hybrids for insulin was approx. 10-fold lower than that of classical insulin receptors, as assessed by inhibition of 125I-insulin binding by unlabelled hormone. It is concluded that the properties of insulin receptors, but not IGF receptors, are markedly affected by assembly as hybrid compared with classical structures, and that hybrids are more likely to be responsive to IGF-I than insulin under physiological conditions.

Effects of passive immunization of growing guinea-pigs with an insulin-like growth factor-I monoclonal antibody

1990 ◽  
Vol 124 (3) ◽  
pp. 403-415 ◽  
Author(s):  
D. E. Kerr ◽  
B. Laarveld ◽  
J. G. Manns
Keyword(s):  
Monoclonal Antibody ◽  
Growth Factor ◽  
Guinea Pigs ◽  
Treated Group ◽  
Insulin Like Growth Factor ◽  
Local Production ◽  
Factor I ◽  
Igf I ◽  
Animal Growth ◽  
Growth Factor I

ABSTRACT The physiological importance of circulating as opposed to locally produced insulin-like growth factor-I (IGF-I) has not been determined. By using a passive immunoneutralization technique, our objectives were to evaluate the role of circulating IGF-I in the regulation of animal growth and pituitary GH content. A monoclonal antibody (MAb) to IGF-I, generated in our laboratory, has an affinity (Ka) of 0·13 litres/pmol for recombinant human IGF-I (rhIGF-I). Cross-reactivities of recombinant des-tripeptide IGF-I and recombinant bovine IGF-II were approximately 40 and 8% respectively. This MAb inhibited binding of purified hIGF-I to human placental membranes. In a radioimmunoassay based on displacement of 125I-labelled rhIGF-I from the MAb, displacement curves generated with dilutions of acid–gel chromatography extracts of guinea-pig serum and rhIGF-I standards were parallel. Twenty-four, 3-week-old male guinea-pigs were treated with the IGF-I MAb, a bovine herpes virus-I (BHV-I) MAb (control MAb) or vehicle (phosphate-buffered saline) (n = 8 per group). Treatments were administered i.p. every 3 days for 24 days at a dose of 20 mg/kg body weight. Blood was obtained on day 23 (48 h after treatment) and on day 25 (24 h after treatment). In a liquid-phase assay, serum from the IGF-I MAb-treated group bound 38 ± 8% (mean ± s.e.m.) (day 23) and 56 ± 7% (day 25) of an 125I-labelled rhIGF-I trace at a final dilution of 1:10 000. Because of the development of an anti-mouse immune response in the guinea-pigs, these parameters would probably have been much greater during the first 2 weeks of the trial. Of the total IGF-I in serum, 50 ± 5% and 61±4% could be immunoprecipitated with an excess of rabbit anti-mouse immunoglobulin in samples from days 23 and 25 respectively. Comparisons between the groups treated with IGF-I MAb and BHV-I MAb revealed no significant differences in whole animal growth rate, growth of individual tissues, or pituitary GH content. Mean serum concentrations of IGF-I were 69 and 99% greater in IGF-I MAb-treated group than in the BHV-I MAb-treated group on days 23 and 25 respectively. These differences probably resulted from an extension of the half-life of IGF-I in serum of animals treated with the IGF-I MAb. The lack of effect of treatment with the IGF-I MAb suggests that local production of IGF-I is generally sufficient to maintain normal growth or that local production or activity of IGF-I is increased in a compensatory fashion. Journal of Endocrinology (1990) 124, 403–415

Sign in / Sign up

Export Citation Format

Share Document