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The HLA-Cw1 and -Cw2 genes were identified in a genomic library and their products characterized by biochemical methods. The HLA-Cw1 and -Cw2 genes, upon transfection in mouse L cells, give rise to class I antigen heavy chains that associate with neither mouse nor human beta-2 microglobulin. They are indistinguishable in isoelectric point from polypeptides identified as HLA-Cw1 and -Cw2 in human cells. The nucleotide sequence of HLA-Cw1 and -Cw2 and their comparison with HLA-Cw3, the only other known HLA-C sequence, reveal a characteristic pattern of locus-specific amino acids. A comparison of 13 different human class I primary structures leads us to speculate that the most variable region in HLA class I antigens, positions 61-83, could assume an alpha helical structure of critical importance for class I antigen function. The locus specificity and the higher degree of intralocus conservation in the COOH-terminal region, especially in the transmembrane and cytoplasmic domains, must reflect evolutionary ancestry rather than positive selection. In view of the pattern and types of substitutions observed for HLA-C locus products, their function as immune response gene products is questioned.

The nucleotide sequences of the human class I major histocompatibility complex genes HLA‐B27k and HLA‐B27w have been determined. They differ by only four nucleotides over a stretch of 14 bp in exon 2, resulting in three amino acid exchanges at positions 77 (Asp to Asn), 80 (Thr to Ile) and 81 (Leu to Ala). The distribution of these nucleotide substitutions suggests a gene conversion‐like event responsible for the generation of these HLA‐B27 subtypes. The mechanisms underlying the generation of new polymorphic variants in man are therefore probably identical to the gene conversion‐like events postulated in the generation of H‐2Kbm class I mutants in the mouse.

Currently, the treatment of non-disseminated solid tumours is performed by surgery and irradiation. Both methods can be considered to be relatively tumour selective, without significantly harming the rest of the body. If however the tumour has disseminated to various organ sites, the metastases can be treated by chemo-or hormone therapy only. Chemotherapy has considerable side effects and a minor influence on patients' survival due to the lack of specificity of action or the induction of resistance. Hormone therapy alone has a limited tumour spectrum.To overcome these obvious limitations of today's treatment modalities, we tailored a fusion gene consisting of the VH and CHI Exons of a humanised MAb and the human P-glucuronidase cDNA . The product encoded by the fusion gene might be suitable for performing an antibody directed enzyme prodrug therapy (ADEPT). The concept of ADEPT as developed by Philpott et al. (1973a,b;1974) and reemphasised by Bagshawe (1987) and Bagshawe et al. (1988) assumes that an antibody enzyme conjugate after selective localisation at the tumour target site, and its clearance from normal tissues, activates a nontoxic low molecular weight prodrug to a highly toxic drug in the tumour by enzymatic catalysis.The therapeutic success of this approach depends on several factors:(a) The stability of the prodrug in vivo. (j) The immunogenicity of the antibody enzyme conjugate. Despite the obvious complexity of the system, a first clinical trial with a F(ab')2 fragment of a murine anti CEA MAb chemically linked to carboxypeptidase G2 (CPG2) from

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