Manuel L Penichet

University of California, Los Angeles, Los Ángeles, California, United States

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Publications (97)396.21 Total impact

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    ABSTRACT: The transferrin receptor 1 (TfR1), also known as CD71, is a target for antibody-based cancer immunotherapy due to its high expression on the surface of cancer cells and its ability to internalize. We have previously developed a mouse/human chimeric IgG3 specific for human TfR1 genetically fused to avidin, as a vector to deliver biotinylated anticancer agents into malignant cells. However, we found that this fusion protein (ch128.1Av), and to a lesser extent the same antibody without avidin (ch128.1), exhibits direct cytotoxic activity in vitro against certain malignant hematopoietic cells through the induction of TfR1 degradation and lethal iron starvation. Importantly, both ch128.1 and ch128.1Av have also shown significant anticancer activity in 2 xenograft models of the B-cell malignancy multiple myeloma. It is interesting to note that ch128.1 exhibited superior anticancer activity in both models compared with ch128.1Av, even against malignant cells that show no sensitivity to ch128.1 in vitro. In the present study, we evaluated the efficacy of ch128.1 against an AIDS-related human Burkitt lymphoma cell line (2F7) to determine if ch128.1 can eliminate these cells in vitro and in an in vivo model of AIDS-related non-Hodgkin lymphoma (AIDS-NHL). Even though 2F7 cells expressed high TfR1 levels, these cells lacked sensitivity to the cytotoxicity induced by ch128.1 in vitro. However, ch128.1 showed significant anticancer activity against these AIDS-NHL cells in vivo by significantly prolonging the survival of immunodeficient mice bearing 2F7 tumors. Therefore, ch128.1 warrants further study as a candidate for the treatment of AIDS-NHL and other B-cell malignancies.
    Journal of immunotherapy (Hagerstown, Md.: 1997) 10/2015; 38(8):307-10. DOI:10.1097/CJI.0000000000000092 · 4.01 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):1335-1335. DOI:10.1158/1538-7445.AM2015-1335 · 9.33 Impact Factor
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    ABSTRACT: The transferrin receptor 1 (TfR1) is involved in cellular iron uptake and regulation of cell proliferation. The increased expression of TfR1 observed in malignant cells, compared to normal cells, together with its extracellular accessibility, make this receptor an attractive target for antibody-mediated cancer therapy. We have developed a mouse/human chimeric IgG3 specific for human TfR1 (ch128.1), which shows anti-tumor activity against certain malignant B cells in vitro through TfR1 degradation and iron deprivation, and in vivo through a mechanism yet to be defined. To further explore potential mechanisms of action of ch128.1, we examined its ability to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC). We now report that ch128.1 is capable of mediating ADCC and CDC against malignant B cells, which is consistent with its ability to bind FcγRI, FcγRIIIa, and the complement component C1q. To delineate the residues involved in these effector functions, we developed a panel of three constructs with mutations in the lower hinge region and CH2 domain: 1) L234A/L235A, 2) P331S, and 3) L234A/L235A/P331S. The triple mutant consistently displayed a significant reduction in ADCC, while the L234A/L235A mutant exhibited less reduction in ADCC, and the P331S mutant did not show reduced ADCC. However, all three mutants exhibited impaired binding to FcγRI and FcγRIIIa. These results suggest that all three residues contribute to ADCC, although to different degrees. The P331S mutant showed drastically decreased C1q binding and abolished CDC, confirming the critical role of this residue in complement activation, while the other residues play a less important role in CDC. Our study provides insights into the effector functions of human IgG3 in the context of an antibody targeting TfR1. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Molecular Immunology 07/2015; 67(2 Pt B). DOI:10.1016/j.molimm.2015.07.001 · 2.97 Impact Factor
  • Lai Sum Leoh · Tracy R Daniels-Wells · Manuel L Penichet
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    ABSTRACT: The success of antibody therapy in cancer is consistent with the ability of these molecules to activate immune responses against tumors. Experience in clinical applications, antibody design, and advancement in technology have enabled antibodies to be engineered with enhanced efficacy against cancer cells. This allows re-evaluation of current antibody approaches dominated by antibodies of the IgG class with a new light. Antibodies of the IgE class play a central role in allergic reactions and have many properties that may be advantageous for cancer therapy. IgE-based active and passive immunotherapeutic approaches have been shown to be effective in both in vitro and in vivo models of cancer, suggesting the potential use of these approaches in humans. Further studies on the anticancer efficacy and safety profile of these IgE-based approaches are warranted in preparation for translation toward clinical application.
    Current topics in microbiology and immunology 01/2015; 388:109-149. DOI:10.1007/978-3-319-13725-4_6 · 4.10 Impact Factor
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    ABSTRACT: We previously developed an antibody-avidin fusion protein (ch128.1Av) specific for the human transferrin receptor 1 (TfR1; CD71) to be used as a delivery vector for cancer therapy and showed that ch128.1Av delivers the biotinylated plant toxin saporin-6 into malignant B cells. However, due to widespread expression of TfR1, delivery of the toxin to normal cells is a concern. Therefore, we explored the potential of dual targeted lentiviral-mediated gene therapy approaches to restrict gene expression to malignant B cells. Targeting occurs through the use of ch128.1Av or its parental antibody without avidin (ch128.1) and through transcriptional regulation using an immunoglobulin promoter. Flow cytometry was used to detect the expression of enhanced green fluorescent protein (EGFP) in a panel of cell lines. Cell viability after specific delivery of the therapeutic gene FCU1, a chimeric enzyme consisting of cytosine deaminase genetically fused to uracil phosphoribosyltransferse that converts the 5-fluorocytosine (5-FC) prodrug into toxic metabolites, was monitored by an MTS assay. We found that EGFP was specifically expressed in a panel of human malignant B cells, but not in human T cell lines. EGFP expression was observed in all cell lines when a ubiquitous promoter was used. Furthermore, we show the decrease of cell viability in malignant plasma cells in the presence of 5-FC. These studies demonstrate that gene expression can be restricted to malignant B cells and suggest that this dual targeted gene therapy strategy may help to circumvent the potential side effects of certain TfR1-targeted protein delivery approaches. This article is protected by copyright. All rights reserved.
    The Journal of Gene Medicine 03/2014; 16(1-2). DOI:10.1002/jgm.2754 · 2.47 Impact Factor
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    ABSTRACT: The availability of mice transgenic for the human HER2 gene (huHER2) and prone to the development of HER2-driven mammary carcinogenesis (referred to as FVB-huHER2 mice) prompted us to study active immunopreventive strategies targeting the human HER2 molecule in a tolerant host. FVB-huHER2 were vaccinated with either IL-12-adjuvanted human HER2-positive cancer cells or DNA vaccine carrying chimeric human-rat HER2 sequences. Onset and number of mammary tumors were recorded to evaluate vaccine potency. Mice sera were collected and passively transferred to xenograft-bearing mice to assess their antitumor efficacy. Both cell and DNA vaccines significantly delayed tumor onset, leading to about 65% tumor-free mice at 70 weeks, whereas mock-vaccinated FVB-huHER2 controls developed mammary tumors at a median age of 45 weeks. In the DNA vaccinated group, 65% of mice were still tumor-free at about 90 weeks of age. The number of mammary tumors per mouse was also significantly reduced in vaccinated mice. Vaccines broke the immunological tolerance to the huHER2 transgene, inducing both humoral and cytokine responses. The DNA vaccine mainly induced a high and sustained level of anti-huHER2 antibodies, the cell vaccine also elicited interferon (IFN)-gamma production. Sera of DNA-vaccinated mice transferred to xenograft-carrying mice significantly inhibited the growth of human HER2-positive cancer cells. Anti-huHER2 antibodies elicited in the tolerant host exert antitumoral activity.
    Breast cancer research: BCR 01/2014; 16(1):R10. DOI:10.1186/bcr3602 · 5.49 Impact Factor
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    ABSTRACT: Despite significant advances in biology and medicine, the incidence and mortality due to breast cancer world-wide is still unacceptably high. Thus, there is an urgent need to discover new molecular targets. In this paper, we show evidence for a novel target in human breast cancer, the tetraspan protein epithelial membrane protein-2 (EMP2). Using tissue tumor arrays, protein expression of EMP2 was measured and found to be minimal in normal mammary tissue, but it was upregulated in 63% of invasive breast cancer tumors and in 73% of triple negative tumors tested. To test the hypothesis that EMP2 may be a suitable target for therapy, we constructed a fully human IgG1 antibody specific for a conserved domain of human and murine EMP2. Treatment of breast cancer cells with the anti-EMP2 IgG1 significantly inhibited EMP2 mediated signaling, blocked FAK/Src signaling, inhibited invasion, and promoted apoptosis in vitro. In both human xenograft and syngeneic metastatic tumor monotherapy models, anti-EMP2 IgG1 retarded tumor growth without detectable systemic toxicity. This anti-tumor effect was in part attributable to a potent ADCC response as well as direct cytotoxicity induced by the monoclonal antibody. Together, these results identify EMP2 as a novel therapeutic target for invasive breast cancer.
    Molecular Cancer Therapeutics 01/2014; 13(4). DOI:10.1158/1535-7163.MCT-13-0199 · 5.68 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):3321-3321. DOI:10.1158/1538-7445.AM2013-3321 · 9.33 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):2848-2848. DOI:10.1158/1538-7445.AM2013-2848 · 9.33 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):1240-1240. DOI:10.1158/1538-7445.AM2013-1240 · 9.33 Impact Factor
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    ABSTRACT: Currently, few rodent models of AIDS-associated non-Hodgkin's lymphoma (AIDS-NHL) exist. In these studies, a novel mouse/human xenograft model of AIDS-associated Burkitt lymphoma (AIDS-BL) was created by injecting cells of the human AIDS-BL cell line, 2F7, intraperitoneally into NOD-SCID mice. Mice developed tumors in the peritoneal cavity, with metastases to the spleen, thymus, and mesenteric lymph nodes. Expression of the chemokine receptor, CXCR5, was greatly elevated in vivo on BL tumor cells in this model, as shown by flow cytometry. CXCL13 is the ligand for CXCR5, and serum and ascites levels of murine, but not human, CXCL13 showed a striking elevation in tumor-bearing mice, with levels as high as 200,000 pg/ml in ascites, as measured by ELISA. As shown by immunohistochemistry, murine CXCL13 was associated with macrophage-like tumor-infiltrating cells that appeared to be histiocytes. Blocking CXCR5 on 2F7 cells with neutralizing antibodies prior to injection into the mice substantially delayed tumor formation. The marked elevations in tumor cell CXCR5 expression and in murine CXCL13 levels seen in the model may potentially identify an important link between tumor-interacting histiocytes and tumor cells in AIDS-BL. These results also identify CXCL13 as a potential biomarker for this disease, which is consistent with previous studies showing that serum levels of CXCL13 were elevated in human subjects who developed AIDS-lymphoma. This mouse model may be useful for future studies on the interactions of the innate immune system and AIDS-BL tumor cells, as well as for the assessment of potential tumor biomarkers for this disease.
    PLoS ONE 08/2013; 8(8):e72414. DOI:10.1371/journal.pone.0072414 · 3.23 Impact Factor
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    ABSTRACT: Multiple myeloma is a non-curable B-cell malignancy in which iron metabolism plays an important role. Patients with this disorder almost universally suffer from clinically significant anemia, which is often symptomatic, and which is due to impaired iron utilization. Recent studies have indicated that the proximal cause of dysregulated iron metabolism and anemia in these patients is cytokine-induced upregulation of hepcidin expression. Malignant myeloma cells are dependent on an increased influx of iron, and therapeutic efforts are being made to target this requirement. The studies detailing the characteristics and biochemical abnormalities in iron metabolism causing anemia and the initial attempts to target iron therapeutically are described in this review.
    Critical reviews in oncogenesis 07/2013; 18(5):449-61. DOI:10.1615/CritRevOncog.2013007934
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    ABSTRACT: Breast cancer remains the second leading cause of cancer death among women in the United States. Breast cancer prognosis is particularly poor in case of tumors overexpressing the oncoprotein HER2/neu. A new nanobioconjugate of the PolycefinTM family of anti-cancer drugs based on biodegradable and non-toxic polymalic acid (PMLA) was engineered for a multi-pronged attack on HER2/neu-positive breast cancer cells. An antibody-cytokine fusion protein consisting of the immunostimulatory cytokine interleukin-2 (IL-2) genetically fused to an antibody specific for human HER2/neu [anti-HER2/neu IgG3-(IL-2)] was covalently attached to the PMLA backbone to target HER2/neu expressing tumors and ensure the delivery of IL-2 to the tumor microenvironment. Antisense oligonucleotides (AON) were conjugated to the nanodrug to inhibit the expression of vascular tumor protein laminin-411 in order to block tumor angiogenesis. It is shown that the nanobioconjugate was capable of specifically binding human HER2/neu and retained the biological activity of IL-2. We also showed the uptake of the nanobioconjugate into HER2/neu-positive breast cancer cells and enhanced tumor targeting in vivo. The nanobioconjugate exhibited marked anti-tumor activity manifested by significantly longer animal survival and significantly increased anti-HER2/neu immune response in immunocompetent mice bearing D2F2/E2 murine mammary tumors that express human HER2/neu. The combination of laminin-411 AON and antibody-cytokine fusion protein on a single polymeric platform results in a new nanobioconjugate that can act against cancer cells through inhibition of tumor growth and angiogenesis and the orchestration of an immune response against the tumor. The present PolycefinTM variant may be a promising agent for treating HER2/neu expressing tumors and demonstrates the versatility of the PolycefinTM nanobioconjugate platform.
    Journal of Controlled Release 06/2013; 171(3). DOI:10.1016/j.jconrel.2013.06.001 · 7.71 Impact Factor
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    ABSTRACT: Background Prostate cancer (PCa) is the second leading cause of cancer deaths in men in the United States. The prostate-specific antigen (PSA), often found at high levels in the serum of PCa patients, has been used as a marker for PCa detection and as a target of immunotherapy. The murine IgG1 monoclonal antibody AR47.47, specific for human PSA, has been shown to enhance antigen presentation by human dendritic cells and induce both CD4 and CD8 T-cell activation when complexed with PSA. In this study, we explored the properties of a novel mouse/human chimeric anti-PSA IgE containing the variable regions of AR47.47 as a potential therapy for PCa. Our goal was to take advantage of the unique properties of IgE in order to trigger immune activation against PCa. Methods Binding characteristics of the antibody were determined by ELISA and flow cytometry. In vitro degranulation was determined by the release of β-hexosaminidase from effector cells. In vivo degranulation was monitored in human FcεRIα transgenic mice using the passive cutaneous anaphylaxis assay. These mice were also used for a vaccination study to determine the in vivo anti-cancer effects of this antibody. Significant differences in survival were determined using the Log Rank test. In vitro T-cell activation was studied using human dendritic cells and autologous T cells. Results The anti-PSA IgE, expressed in murine myeloma cells, is properly assembled and secreted, and binds the antigen and FcεRI. In addition, this antibody is capable of triggering effector cell degranulation in vitro and in vivo when artificially cross-linked, but not in the presence of the natural soluble antigen, suggesting that such an interaction will not trigger systemic anaphylaxis. Importantly, the anti-PSA IgE combined with PSA also triggers immune activation in vitro and in vivo and significantly prolongs the survival of human FcεRIα transgenic mice challenged with PSA-expressing tumors in a prophylactic vaccination setting. Conclusions The anti-PSA IgE exhibits the expected biological properties and is capable of triggering immune activation and anti-tumor protection. Further studies on this antibody as a potential PCa therapy are warranted.
    BMC Cancer 04/2013; 13(1):195. DOI:10.1186/1471-2407-13-195 · 3.36 Impact Factor
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    ABSTRACT: We previously developed an antibody-avidin fusion protein (ch128.1Av) that targets the human transferrin receptor 1 (TfR1) and exhibits direct cytotoxicity against malignant B cells in an iron-dependent manner. ch128.1Av is also a delivery system and its conjugation with biotinylated saporin (b-SO6), a plant ribosome-inactivating toxin, results in a dramatic iron-independent cytotoxicity, both in malignant cells that are sensitive or resistant to ch128.1Av alone, in which the toxin effectively inhibits protein synthesis and triggers caspase activation. We have now found that the ch128.1Av/b-SO6 complex induces a transcriptional response consistent with oxidative stress and DNA damage, a response that is not observed with ch128.1Av alone. Furthermore, we show that the antioxidant N-acetylcysteine partially blocks saporin-induced apoptosis suggesting that oxidative stress contributes to DNA damage and ultimately saporin-induced cell death. Interestingly, the toxin was detected in nuclear extracts by immunoblotting, suggesting the possibility that saporin might induce direct DNA damage. However, confocal microscopy did not show a clear and consistent pattern of intranuclear localization. Finally, using the long-term culture-initiating cell assay we found that ch128.1Av/b-SO6 is not toxic to normal human hematopoietic stem cells suggesting that this critical cell population would be preserved in therapeutic interventions using this immunotoxin.
    Toxicology in Vitro 10/2012; 27(1). DOI:10.1016/j.tiv.2012.10.006 · 2.90 Impact Factor
  • Ana Rocha · Lei Wang · Manuel Penichet · Manuela Martins-Green
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    ABSTRACT: Breast cancer is the most common cancer and the second leading cause of cancer death and morbidity among women in the western world. Pomegranate juice (PJ) and three of its specific components have been shown to inhibit processes involved in prostate cancer metastasis. If this also proves to be true for breast cancer, these natural treatments will be promising agents against breast cancer that can serve as potentially effective and nontoxic alternatives or adjuncts to the use of conventional selective estrogen receptor modulators for breast cancer prevention and treatment. To test this possibility, we have used two breast cancer cell lines, MDA-MB-231 cells (ER(-)) and MCF7 (ER(+)), and the non-neoplastic cell line MCF10A. We show that, in addition to inhibiting growth of the breast cancer cells, PJ or a combination of its components luteolin (L) + ellagic acid (E) + punicic acid (P) increase cancer cell adhesion and decrease cancer cell migration but do not affect normal cells. These treatments also inhibit chemotaxis of the cancer cells to SDF1α, a chemokine that attracts breast cancer cells to the bone. We hypothesized that PJ and L + E + P stimulate expression of genes that increase adhesion and inhibit genes that stimulate cell migration and inhibit chemotaxis to SDF1α. Using qPCR, we confirmed these proposed effects on gene expression and in addition we found that a gene important in epithelial-to-meshenchymal transitions is decreased. We also found that pro-inflammatory cytokines/chemokines are significantly reduced by these treatments, thereby having the potential to decrease inflammation and its impact on cancer progression. Discovery that PJ and L + E + P are inhibitory of metastatic processes in breast cancer cells in addition to prostate cancer cells indicate that they are potentially a very effective treatment to prevent cancer progression in general.
    Breast Cancer Research and Treatment 10/2012; 136(3). DOI:10.1007/s10549-012-2264-5 · 3.94 Impact Factor
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    ABSTRACT: Multiple myeloma (MM) is an incurable B-lymphocyte malignancy. New therapeutic options have become available during the past several years; however nearly all patients acquire resistance to currently available therapeutic agents. Mechanisms contributing to the pathogenesis and chemoresistance of MM include genetic abnormalities, chromosomal translocations, gene mutations, the interaction between MM cells and the bone marrow microenvironment, and defects in the apoptotic signaling pathways. Survival signaling pathways associated with the pathogenesis of MM and bone marrow stromal cells play crucial roles in promoting growth, survival, adhesion, immortalization, angiogenesis, and drug resistance. The receptor activator of nuclear factor-kappa B/receptor activator of nuclear factor-kappa B ligand/tumor necrosis factor receptor-associated factor (RANK/RANKL-TRAF6) signal pathway mediates osteolytic bone lesions through the activation of the NF-κB and Janus kinase/signal transducer and activator of transcription (JNK) pathways in osteoclast precursor cells and thus contributes to the main clinical manifestations of bone disease. TRAF6 has also been identified as a ligase for Akt ubiquitination and membrane recruitment and its phosphorylation on growth factor stimulation. The inhibition of TRAF6 by silencing RNA or by decoy peptides decreases MM tumor cell proliferation and increases apoptosis as well as bone resorption. Some proteasome inhibitors and benzoxadiazole derivatives showed inhibitory effects on the activity and function of TRAF6. Overall, we propose that TRAF6 may be considered as a potential therapeutic target for the treatment of MM.
    Clinical lymphoma, myeloma & leukemia 03/2012; 12(3):155-63. DOI:10.1016/j.clml.2012.01.006 · 2.02 Impact Factor
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    ABSTRACT: Five New World (NW) arenaviruses cause human hemorrhagic fevers. Four of these arenaviruses are known to enter cells by binding human transferrin receptor 1 (hTfR1). Here we show that the fifth arenavirus, Chapare virus, similarly uses hTfR1. We also identify an anti-hTfR1 antibody, ch128.1, which efficiently inhibits entry mediated by the glycoproteins of all five viruses, as well as replication of infectious Junín virus. Our data indicate that all NW hemorrhagic fever arenaviruses utilize a common hTfR1 apical-domain epitope and suggest that therapeutic agents targeting this epitope, including ch128.1 itself, can be broadly effective in treating South American hemorrhagic fevers.
    Journal of Virology 01/2012; 86(7):4024-8. DOI:10.1128/JVI.06397-11 · 4.44 Impact Factor
  • Tracy R Daniels · Otoniel Martínez-Maza · Manuel L Penichet
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    ABSTRACT: Although most monoclonal antibodies developed for cancer therapy are of the IgG class, antibodies of the IgE class have certain properties that make them attractive as cancer therapeutics. These properties include the superior affinity for the Fc epsilon receptors (FcεRs), the low serum level of IgE that minimizes competition of endogenous IgE for FcεR occupancy, and the ability to induce a broad and vigorous immune response through the interaction with multiple cells including mast cells, basophils, monocytes, macrophages, dendritic cells, and eosinophils. Tumor-targeted IgE antibodies are expected to harness the allergic response against tumors and activate a secondary, T-cell-mediated immune response. Importantly, the IgE antibody can be used for passive immunotherapy and as an adjuvant of cancer vaccines. However, there are important limitations in the use of animal models including the fact that human IgE does not interact with rodent FcεRs and that there is a different cellular distribution of FcεRs in humans and rodents. Despite these limitations, different murine models have been used with success to evaluate the in vivo anti-cancer activity of several IgE antibodies. These models include wild-type immunocompetent animals bearing syngeneic tumors, xenograft models using immunocompromised mice bearing human tumors and reconstituted with human effector cells, and human FcεRIα transgenic mice bearing syngeneic tumors. In addition, non-human primates such as cynomolgus monkeys can be potentially used for toxicological and pharmacokinetic studies. This article describes the advantages and disadvantages of these models and their use in evaluating the in vivo properties of IgE antibodies for cancer therapy.
    Cancer Immunology and Immunotherapy 12/2011; 61(9):1535-46. DOI:10.1007/s00262-011-1169-1 · 3.94 Impact Factor

Publication Stats

2k Citations
396.21 Total Impact Points


  • 1998–2015
    • University of California, Los Angeles
      • • Department of Surgery
      • • Division of Surgical Oncology
      • • Jonsson Comprehensive Cancer Center
      • • Department of Microbiology, Immunology, and Molecular Genetics
      • • Molecular Biology Institute
      Los Ángeles, California, United States
  • 2011
    • Cedars-Sinai Medical Center
      • Cedars Sinai Medical Center
      Los Angeles, CA, United States
  • 1970–2011
    • California State University
      • Molecular Ecology Institute
      Long Beach, California, United States
  • 2010
    • Keio University
      • Department of Urology
      Tokyo, Tokyo-to, Japan
  • 2008–2009
    • CSU Mentor
      Long Beach, California, United States