Immunotargeting of tumors: state of the art and prospects in 2000

Following 15 years of experimental studies, tumor immunotargeting using monoclonal antibodies directed against tumor associated antigens shows now important monoclonal antibodies directed against tumor associated antigens shows now important clinical developments. This is mainly due to encouraging therapeutic results which have obtained using humanized antibodies such as the anti-CD20 rituximab in follicular B lymphomas and the anti-DrbB2 herceptin in breast carcinomas. Thanks to genetic engineering it is possible to graft variable or hypervariable regions from murine antibodies to human IgG, and even to obtain fully human antibodies by using either transgenic mice containing a large part of the human repertoire of human IgG, or selection of human antibody fragments expressed by phages. Radiolabeling of antibodies played a major role to demonstrate the tumor immunotargeting specificity and remains attractive for the diagnosis by immunoscintigraphy as well as for the treatment by radioimmunotherapy of some cancers. In this review, the current results and the prospects of diagnostic and therapeutic uses of anti-tumor antibodies and their fragments will be described. Concerning diagnosis, 123-iodine or 99m-technetium labeled Fab fragments allowed very demonstrative tumor images but this technique has a limited effect upon the therapeutic attitude. Immuno-PET (positron emission tomography) could enhance the sensitivity of this imaging method. Radio-immunoguided surgery and immunophotodetection are attractive techniques still under evaluation. Concerning therapy, 131-iodine labeled anti-CD20 antibodies gave spectacular results in non-Hodgkin's B lymphomas. In solid tumors which as less radiosensitive, radioimmunotherapy could concern small tumors and need the use of two-steps targeting and/or alpha emitters radioisotopes. Some other strategies will be described such as bispecific antibodies directed against tumors and immune effector cells, some antibody fragments expressed on T cells called T-bodies or some biological studies using intrabodies. Published data and works in progress demonstrate that immunotargeting of tumors will have a growing place in the treatments of cancer patients.     

Bone mineral content measurement: reflections on the equipment]

Metabolic bone disorders are extremely interesting from an epidemiological, clinical and social point of view. In particular, some of them are important for they are typical of elderly people--i.e., the portion of population which is on the increase due to the lengthening of the average life. On the other hand, thanks to the current intervention techniques, the number of chronic nephropathics (in whom metabolic bone conditions may develop) has markedly increased. Therefore, sufficiently reliable methods are needed to allow the thorough evaluation of bone mineral components. Unfortunately, these methods are only of quantitative value because they are unable to discriminate the statuses of the two essential bone components--i.e., cortex and spongiosa--; we all know that bone mineral loss can currently be quantified only when amounting to < 20% of the total value, due to the addition of the mineral contents of the two components. In this paper the authors briefly report on the noninvasive techniques currently in use for the measurement of bone mineral components, especially relative to their physical bases, the knowledge of which is essential for a correct evaluation. The authors accurately reviewed the literature data relative to the various techniques and compared the results obtained by the different authors. Thus, no personal experience is reported, since this paper is aimed at being considered as a reference mark for the reader to be helped in the choice of the equipment suiting him most. However, as to preventing metabolic osteopathies, quantitative methods cannot yield absolute data, which addresses the current research to densitometry by means of the Compton method. The latter may finally lead to the development of operative equipment allowing not only the separate measurement of cortical and spongiose values, but also the qualitative evaluation of bone status--i.e., not limited to mineral loss but including also the determination of the protein, fat and water components.     

Selective modification of NMR relaxation time in human colorectal carcinoma by using gadolinium-diethylenetriaminepentaacetic acid conjugated with monoclonal antibody 19-9.

Monoclonal antibody 19-9 (mAb 19-9) against human colon adenocarcinoma was conjugated with gadolinium X diethylenetriaminepentaacetic acid (Gd X DTPA) and used as a contrast agent in nuclear magnetic resonance (NMR) in an effort to improve tumor target selectivity in nude mice. The data indicate that Gd X DTPA-mAb 19-9 in solution decreased the T1 relaxation of water protons at 90 MHz in direct proportion to the gadolinium concentration, and this effect was greater than in Gd X DTPA solutions. T1 relaxation time at 90 MHz, measured in tumors removed from nude mice 24 hr after injection of Gd X DTPA-mAb 19-9 (Gd, 20 mumol/kg; 16 DTPA molecules per mAb molecule), was significantly decreased (by 15%) as compared with the control group. Similar results were obtained in tumors from mice injected with Gd X DTPA-mAb 19-9 solutions in which Gd was used at 2, 6, or 10 mumol/kg (16 DTPA molecules per mAb molecule). These doses are lower than those commonly used for Gd X DTPA (10-100 mumol/kg) as contrast agent. Tumor localization by the Gd X DTPA-mAb 19-9 complex containing radioactive Gd (0.3 microCi/microgram of 153Gd) to confirm scintigraphy revealed significant concentrations of the complex (5% of the injected dose per gram of tissue) in the tumor. Scan images recorded in planar scintigraphy at day 5 showed good visualization of tumors.     

Radiolabelled monoclonal antibodies against alpha-fetoprotein for in vivo localization of human hepatocellular carcinoma by immunotomoscintigraphy

Two high affinity monoclonal antibodies, designated AF01 and AF04, directed against distinct epitopes of human alpha-fetoprotein (AFP) and the Fab fragments of one of them, were labelled with 131I and injected into 18 patients with AFP producing hepatocellular carcinoma (HCC) in order to carry out imaging studies by tomoscintigraphy. Twelve patients were injected with whole antibody, only three of seven patients injected with AF01 and two of five patients injected with AF04 had a positive scan. In contrast, five out of six patients injected with labelled Fab fragments of AF04 had positive imaging. These results confirm that tumour imaging of HCC using 131I labelled monoclonal antibody against AFP is feasible. Moreover, utilization of tomoscintigraphy in place of linear scintigraphy and Fab fragments instead of whole immunoglobulin may improve the sensitivity of radioimmunolocalization. This technique provides useful information on the in vivo distribution of monoclonal antibodies directed against AFP and on the practicability of the eventual therapeutic use of anti-AFP antibodies in HCC.     

Assessment of body plantar pressure in elite athletes: an observational study

An intense program of physical activity, typical of elite athletes, results in a series of modifications of the posture that in a short period of time can have a negative impact on both their health and performance. These negative effects can be prevented and corrected by an integrated approach that encompasses anthropometry and posture evaluation. The aim of this study is the assessment of the anthropometric and postural parameters of elite athletes of different sports specialities to identify discipline(s) potentially associated with unbalanced postural attitudes. Height, weight, body mass index, stabilometric analysis, foot load, and center of pressure distribution were evaluated to identify which parameters are mainly correlated with postural aspects in professional athletes compared to amateur, age-matched subjects. We found a permanently unbalanced postural attitude in rugby players, skiers, and judokas, which are not, by definition, asymmetric sport disciplines. On the contrary, motorcyclists showed an overall balanced load distribution, probably due to the absence of any special performance required from lower limbs, potentially forcing a specific postural shape. This data is the basis to identify anthropometric and postural parameters mostly modified in different sport disciplines, which need to be always monitored to counteract the establishment of sport-specific imbalances.     

Initial results in man of immunolymphoscintigraphy of cancer of the prostate

The loco-regional investigation of carcinoma of the prostate usually comprises ilio-obturator lymphadenectomy. This procedure carries a significant morbidity. Immunolymphoscintigraphy may provide a non-invasive alternative to this operation. Monoclonal (MAB) 227 A anti-prostatic acid phosphatase antibodies have been produced and selected for their affinity and specificity. This MAB was fragmented to its F (ab')2 form and marked with Iodine 123. Fifteen patients with prostate cancer were given 100 to 400 micrograms of the MAB by periprostatic perineal injection. The region was scanned 1 hr, 3 hrs, 6 hrs and 24 hrs after the injection. The results of the immunolymphoscintigraphy were compared with the histology of the ganglia removed at surgery or needle biopsy guided by CT scanning. In 13 cases the results were concordant for the two techniques (10 negatives and 3 positives). Two patients showed extra-prostatic fixation whilst the histology remained negative. Immunolymphoscintigraphy may therefore provide a simple method of detecting local metastases of carcinoma of the prostate if these initial results are confirmed.     

Radioimmunodetection of lymph node invasion in prostatic cancer. The use of iodine 123 (123I)-labeled monoclonal anti-prostatic acid phosphatase (PAP) 227 A F(ab')2 antibody fragments in vivo

The therapeutic indications in prostatic cancer depend on the regional and distant extension of the cancer and are difficult to assess before lymphadenectomy. Radioimmunodetection of lymph node involvement with monoclonal anti-prostatic acid phosphatase (PAP) antibodies can be proposed as a noninvasive alternative to lymphadenectomy. Fifteen patients with various stages of histologically proven prostatic cancer were examined by immunolymphoscintigraphy (ILS) before treatment to detect lymph node metastases. These patients had Stage A (n = 7), Stage B (n = 3), Stage C (n = 2), and Stage D (n = 3) tumors. They received between 100 and 400 micrograms of monoclonal antibody 227 A in the form of F(ab')2 fragments labeled with iodine 123 (123I). The antibody was injected directly into the periprostatic area. ILS images were obtained after 1, 3, 6, and 24 hours. Three days later, each patient underwent a lymphadenectomy for histologic examination. The results of the histologic examination and ILS were compared. In ten patients, the examination did not show any images capable of being interpreted as lymphadenopathy and histologic examination confirmed the integrity of the nodes examined. In five cases, scintigraphy suggested the presence of lymph node invasion by prostatic cancer and this was confirmed by histologic examination in three of the five cases. Overall, in terms of lymphadenopathy, this examination had a sensitivity of 100% and a specificity of 83%. Therefore, ILS appears to be capable of detecting lymph node metastases in prostatic cancer.     

Immunoscintigraphy of recurrences of gynecologic carcinomas

In a first, retrospective study, 15 patients with known ovarian carcinoma were injected with 131I-OC 125 F(ab')2 monoclonal antibody (MAb). The sensitivity of immunoscintigraphy based on the number of the tumor sites was 67% (12/18). In a second, prospective study, 29 patients with gynecologic carcinoma were injected with 131I-OC 125 F(ab')2 (24) or 131I-19-9 F(ab')2 (5) MAbs according to the histologic type. Based on the number of tested anatomic sites, sensitivity was 72% and specificity 86%. In two patients injected with both 131I-OC-125 F(ab')2 and 125I-NS F(ab')2 (nonspecific immunoglobulin) 1 and 4 days before tumor resection, tumor uptake of the specific antibody was 2.2 and 4.5 times greater than that of NS. Immunoscintigraphic results were complementary with those of ultrasonography and computed tomography. Finally, in one patient injected successively with 131I-OC 125 F(ab')2 and 111In-DTPA-OC 125 F(ab')2, the recurrent tumor was visualized with both radionuclides, with 111In providing better abdominal tumor contrast but causing much greater liver radioactivity than 131I.