Purpose: Geographic atrophy (GA), a late stage of age-related macular degeneration (AMD), is a major cause of blindness. Even while central visual acuity remains relatively well preserved, GA often causes considerable compromise of visual function and quality of life. No treatment currently exists. We evaluated the safety and efficacy of pegcetacoplan, a complement C3 inhibitor, for treatment of GA. Design: Prospective, multicenter, randomized, sham-controlled phase 2 study. Participants: Two hundred forty-six patients with GA. Methods: Patients with GA were assigned randomly in a 2:2:1:1 ratio to receive intravitreal injections of 15 mg pegcetacoplan monthly or every other month (EOM) or sham intravitreal injections monthly or EOM for 12 months with follow-up at months 15 and 18. Area and growth of GA were measured using fundus autofluorescence imaging. Main Outcome Measures: The primary efficacy end point was mean change in square root GA lesion area from baseline to month 12. Secondary outcome measures included mean change from baseline in GA lesion area without the square root transformation, distance of GA lesion from the fovea, best-corrected visual acuity (BCVA), low-luminance BCVA, and low-luminance visual acuity deficit. The primary safety end point was the number and severity of treatment-emergent adverse events. Results: In patients receiving pegcetacoplan monthly or EOM, the GA growth rate was reduced by 29% (95% confidence interval [CI], 9e49; P ¼ 0.008) and 20% (95% CI, 0e40; P ¼ 0.067) compared with the sham treatment group. Post hoc analysis showed that the effect was greater in the second 6 months of treatment, with observed reductions of 45% (P ¼ 0.0004) and 33% (P ¼ 0.009) for pegcetacoplan monthly and EOM, respectively. Two cases of culture-positive endophthalmitis and 1 case of culture-negative endophthalmitis occurred in the pegcetacoplan monthly group. New-onset investigator-determined exudative AMD was reported more frequently in pegcetacoplan-treated eyes (18/86 eyes [20.9%] and 7/79 eyes [8.9%] in monthly and EOM groups, respectively) than in sham-treated eyes (1/81 eyes [1.2%]). Conclusions: Local C3 inhibition with pegcetacoplan resulted in statistically significant reductions in the growth of GA compared with sham treatment. Phase 3 studies will define the efficacy and safety profile further.

Studies of the temperature-sensitive cdc37-1 mutant of Saccharomyces cerevisiae suggest that Cdc37 is required for passage through the G1 phase of the cell cycle, but its precise function is not known. We have investigated the role of Cdc37 in the regulation of the cyclin-dependent protein kinase Cdc28. We find that G1 arrest in the cdc37-1 mutant is accompanied by a decrease in the Cdc28 activity associated with the G1 cyclin Cln2 (3,4). Mutations in CDC36 and CDC39 result in constitutive activation of the mating pheromone pathway (5), whereas CDC28 is more directly involved in cell cycle control (1, 2, 6).The function of CDC37 is unknown.The product of the CDC28 gene is a member of the highly conserved family of cyclin-dependent kinases (CDKs), whose activation at specific cell cycle stages requires association with cyclin regulatory subunits (2,(7)(8)(9). The commitment to a new cell division cycle in G1 is controlled by complexes of Cdc28 and the G1 cyclins Clnl, -2, and -3. G1 arrest by mating pheromone involves inhibition of specific Cdc28-Cln complexes and decreased synthesis of Clnl and Cln2. Cdc28 function is also required later in the cell cycle: progress through S phase and mitosis requires activation of Cdc28 by S-phase cyclins (Clb5 and -6) and mitotic cyclins (Clbl, -2, -3, and -4), respectively (see ref For a-factor arrest, 120-ml cultures were grown at 24°C to an OD600 of 0.5. a-Factor (1.0 tLg/ml) was added for 2 hr. For mitotic arrest, 25-ml cultures were grown at 24°C to an OD600 of 0.3. Cells were transferred to medium containing benomyl (60 ,ug/ml) and nocodazole (20 ,g/ml) for 2 hr at 24°C.A 5.8-kb genomic DNA fragment containing the CDC37 gene was a gift of S. Reed (Scripps Institute, La Jolla, CA). To construct the cdc37A allele, a fragment of CDC37 (coding for aa Figs. 1-3, logarithmic-phase cells were resuspended in 700 ptl of ice-cold 20 mM Tris-HCl, pH 7.4/0.1% Triton X-100/100 mM NaCl/5 mM EDTA/50 mM P-glycerophosphate/50 mM NaF/1 mM phenylmethylsulfonyl fluoride/1 mM dithiothreitol with aprotinin (2 ,tg/ml) and leupeptin (1 tLg/ml). One milliliter of glass beads was added, and cells were lysed at 4°C by two pulses (60 s) in a miniBeadBeater (Biospec Products, Bartlesville, OK). Lysates were clarified by centrifugation at 14,000 x g for 10 min at 4°C. In Fig. 4

Retinoblastoma is a childhood tumor that can arise because of mutant alleles acquired as somatic or germinal mutations. The mutant allele can be carried in the germ line. The mutations creating these alleles act by inactivating copies of a recessive oncogene located within band q14 of chromosome 13 and termed the RB1 locus. We have reported isolation of a cDNA fragment that recognizes chromosomal sequences possessing many of the attributes of the retinoblastoma gene associated with the RB1 locus. We now report that this segment is additionally the target of somatic mutations in mesenchymal tumors among patients having no apparent predisposition to retinoblastoma and no previous evidence of retinoblastoma. These tumors provide additional evidence that the cloned sequences are representative of a gene that is a frequent target of inactivation during tumorigenesis. Sequence analysis of this cDNA provides little insight into its normal functional role.

We have isolated a cDNA clone of the murine homologue of the human retinoblastoma (Rb) susceptibility gene. DNA sequence analysis reveals a high degree of conservation with the human Rb sequence, both in the coding and in the noncoding regions. The predicted amino acid sequence of the mouse Rb protein shows 91% identity to that of the human protein. Both proteins were found to contain a peptide sequence reminiscent of a leucine-repeat motif ("leucine-zipper") that is also found in the myc, fos, and jun oncogenes. Synthetic peptide antiserum directed against a portion of the mouse Rb protein detects three proteins of 104-110 kDa in cells that were transiently transfected with a mouse Rb gene expression construct. In the mouse embryo the expression of Rb mRNA was ubiquitous, with maximal expression being observed around 13 days of gestation. In the embryo, the highest level of expression was observed in liver and brain. In contrast, the Rb gene was found to be expressed at a very low level in adult mouse liver with high levels being found in lung, thymus, and spleen. A shorter Rb transcript was detected in mouse testes.

The role of complement in cancer has received increasing attention over the last decade. Recent studies provide compelling evidence that complement accelerates cancer progression. Despite the pivotal role of complement in fighting microbes, complement seems to suppress antitumor immunity via regulation of host cell in the tumor microenvironment. Although most studies link complement in cancer to complement activation in the extracellular space, the discovery of intracellular activation of complement, raises the question: what is the relevance of this process for malignancy? Intracellular activation is pivotal for the survival of immune cells. Therefore, complement can be important for tumor cell survival and growth regardless of the role in immunosuppression. On the other hand, because intracellular complement (the complosome) is indispensable for activation of T cells, these functions will be essential for priming antitumor T cell responses. Here, we review functions of complement in cancer with the consideration of extra and intracellular pathways of complement activation and spatial distribution of complement proteins in tumors and periphery and provide our take on potential significance of complement as biomarker and target for cancer therapy.