Therapeutic Lymphoma Idiotype Vaccine Generated in Insect Cells Results in Mannose Receptor Targeting and Enhanced Immune Activation David J. Betting,

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Therapeutic Lymphoma Idiotype Vaccine Generated in Insect Cells Results in Mannose Receptor Targeting and Enhanced Immune Activation David J. Betting, Xi Y. Mu, Kamran Kafi, Desmond McDonnel, Francisco Rosas, Daniel P. Gold, and John M. Timmerman Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia

Therapeutic Lymphoma Idiotype Vaccine Generated in Insect Cells Results in Mannose Receptor Targeting and Enhanced Immune Activation Treatment of lymphoma patients with tumor-specific immunoglobulin (idiotype, Id) coupled to the immunogenic carrier protein keyhole limpet hemocyanin (Id-KLH) has shown promising results in phase 2 clinical trials However, vaccines fail to elicit anti-Id immune responses in some patients, thus prompting the search for ways to improve the immunogenicity of Id-KLH vaccines Background Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia.

Therapeutic Lymphoma Idiotype Vaccine Generated in Insect Cells Results in Mannose Receptor Targeting and Enhanced Immune Activation Current Id vaccine trials utilize tumor-specific Id proteins secreted by tumor-myeloma hybridomas, or recombinant Id proteins produced in mammalian lymphoid cells, bacteria, or insect cells Recombinant proteins produced in insect cells are reported to have altered glycosylation patterns (terminal mannose residues) that may contribute to immunogenicity, but direct comparisons of insect-derived and mammalian-derived tumor antigens are lacking Background Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia.

Therapeutic Lymphoma Idiotype Vaccine Generated in Insect Cells Results in Mannose Receptor Targeting and Enhanced Immune Activation To determine if terminal mannose carbohydrate structures, characteristic of recombinant proteins produced in insect cells, lead to Id proteins with significantly enhanced immunostimulatory properties compared to Id proteins derived from mammalian sources We sought to systematically compare the immunogenic properties of insect cell-derived vs. mammalian cell- derived Id proteins in murine B cell lymphoma model and in cultures of human antigen-presenting dendritic cells Objective Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia.

Glycosylation Patterns of A20 Id Made in Insect Cells Vs. Mammalian Cells Figure 1: Insect and hybridoma derived A20 Id proteins were analyzed by the cIEF and CE carbohydrate methods. Only insect cell- dervied Id has a high content of terminal mannose residues Materials & Methods Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia.

Therapeutic Lymphoma Idiotype Vaccine Generated in Insect Cells Results in Mannose Receptor Targeting and Enhanced Immune Activation Monocyte-derived human dendritic cells (DCs) were incubated with fluorescently labeled Id proteins produced in insect or mammalian cell cultures Methods Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia.

Therapeutic Lymphoma Idiotype Vaccine Generated in Insect Cells Results in Mannose Receptor Targeting and Enhanced Immune Activation Insect cell-derived Id demonstrated substantially higher binding to DCs compared to the Id from a mammalian source by flow cytometry, and only the insect cell Id showed reduced binding when the DCs were preincubated with mannose receptor inhibitors These results demonstrated that the insect cell-derived Id resulted in better targeting to DCs compared to the mammalian Id Results Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia.

Insect Derived Idotype Proteins Bind to Mannose Receptors on Human Dendritic Cells Figure 2A: DC binding of FITC labeled KLH, hybridoma produced (Hyb) human IgG, and insect derived (BV) human IgG showed some binding of KLH, but no binding of human IgG (Hyb). Human IgG (BV) did show a strong signal for binding to human DCs. Binding of FITC labeled insect (BV) or hybridoma (Hyb) derived human IgG proteins Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia.

Insect Derived Idotype Proteins Bind to Mannose Receptors on Human Dendritic Cells Figure 2B: 50 µg of Alexa 647 labeled murine A20 Id produced in BV or Hyb were used to stain monocyte derived human DCs along with free Alexa. Insect derived Id shows substantially higher surface binding compared to hybridoma derived Id or unconjugated Alexa 647. Binding of FITC labeled insect (BV) or hybridoma (Hyb) derived A20 Id proteins Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia.

Insect Derived Idotype Proteins Bind to Mannose Receptors on Human Dendritic Cells Figure 2C: 50 µg of BV derived A20 Id, hybridoma derived A20 Id, or FITC-dextran were used to stain human DCs in the presence of various inhibitors. Cells were pretreated for 20 minutes with 3 mg/ml of mannan, 50 µg/ml of control IgG blocking antibody, 50 µg/ml of anti-mannose receptor blocking antibody, or 5 µg/ml of cytochalasin D. The blocking agents, with the exception of cytochalasin D, did not cause decreased binding of the hybridoma derived Id. In contrast, the BV derived A20 Id protein and the FITC-dextran both showed decreases in binding in the presence of all the various inhibitors. Binding of Alexa 647 labeled insect (BV) or hybridoma (Hyb) derived A20 Id proteins Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia.

Therapeutic Lymphoma Idiotype Vaccine Generated in Insect Cells Results in Mannose Receptor Targeting and Enhanced Immune Activation When insect cell-derived Id proteins were coupled to KLH using glutaraldehyde and co-cultured with immature human DCs, increased expression of CD80 and CCR7 was observed by flow cytometry, indicating DC maturation Upregulation of these markers was blocked by pre-treatment with anti-mannose receptor antibody Results Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia.

Insect-Derived Idiotype Enhances Upregulation of Human Dendritic Cell Activation Markers Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia. CD MFI Media only Id-KLH (BV) 50 µg Id-KLH (Hyb) 50 µg Id-KLH (BV) 100 µg Id-KLH (Hyb) 100 µg P= P= Figure 3A: Insect derived Id proteins stimulate expression of DC activation markers over that seen with hybridoma-derived (Hyb) Id. The MFIs for CD80 was significantly upregulated with the BV-derived Id conjugates compared to Hyb-derived conjugates.

Insect-Derived Idiotype Enhances Upregulation of Human Dendritic Cell Activation Markers Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia. CCR MFI P= P= Media only Id-KLH (BV) 50 µg Id-KLH (Hyb) 50 µg Id-KLH (BV) 100 µg Id-KLH (Hyb) 100 µg Figure 3B: Insect derived Id proteins stimulate expression of DC activation markers over that seen with hybridoma-derived (Hyb) Id. The MFIs for CD80 was significantly upregulated with the BV-derived Id conjugates compared to Hyb-derived conjugates.

Insect-Derived Idiotype Enhances Upregulation of Human Dendritic Cell Activation Markers Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia. CD MFI Experimental / MFI Media Alone P= P= Id-KLH (BV) 50 µg Id-KLH (Hyb) 50 µg Id-KLH (BV) 100 µg Id-KLH (Hyb) 100 µg Figure 3C: CD80 surface expression levels are represented as MFI of experimental sample/MFI of media alone.

Insect-Derived Idiotype Enhances Upregulation of Human Dendritic Cell Activation Markers Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia. P= CCR MFI Experimental / MFI Media Alone Id-KLH (BV) 50 µg Id-KLH (Hyb) 50 µg Id-KLH (BV) 100 µg Id-KLH (Hyb) 100 µg P= Figure 3D: CCR7 surface expression levels are represented as MFI of experimental sample/MFI of media alone.

Blocking Mannose Receptor Inhibits the Upregulation of Human Dendritic Cell Activation Markers Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia. Donor µg 50 µg 50 µg + anti-MR 100 µg 100 µg + anti-MR CD µg 50 µg 50 µg + anti-MR 100 µg 100 µg + anti-MR CCR7 Media only Id-KLH (BV) Id-KLH (Hyb) MFI Figure 4: Surface expression of CD80 and CCR7 were evaluated after incubation with BV- or Hyb-derived conjugates with or without pretreatment using 50 µg/ml of anti-MR blocking antibody. The BV-conjugate treated sample showed a marked decrease in surface expression of both CD80 and CCR7 with anti-MR pretreatment.

Blocking Mannose Receptor Inhibits the Upregulation of Human Dendritic Cell Activation Markers Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia µg 50 µg 50 µg + anti-MR 100 µg 100 µg + anti-MR CD µg 50 µg 50 µg + anti-MR 100 µg 100 µg + anti-MR CCR7 Donor 2 MFI Media only Id-KLH (BV) Id-KLH (Hyb) Figure 4: Surface expression of CD80 and CCR7 were evaluated after incubation with BV- or Hyb-derived conjugates with or without pretreatment using 50 µg/ml of anti-MR blocking antibody. The BV-conjugate treated sample showed a marked decrease in surface expression of both CD80 and CCR7 with anti-MR pretreatment.

Therapeutic Lymphoma Idiotype Vaccine Generated in Insect Cells Results in Mannose Receptor Targeting and Enhanced Immune Activation In tumor therapy studies, mice with 4-day established A20 murine B cell lymphoma were treated with 3 weekly injections of Id-KLH plus GM-CSF and followed for survival A20 bearing mice treated with Id-KLH containing insect cell-derived A20 Id displayed improved survival compared with mice treated with hybridoma-derived A20 Id-KLH (61% vs. 46%, respectively) Results Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia.

Tumor Eradication is Superior with Use of Insect-Derived Idiotype Proteins Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia. Individual A20-KLH (BV) and (Hyb) Groups Using Each Conjugation Method A20-KLH (Hyb) Mal A20-KLH (BV) Glut A20-KLH (Hyb) Glut Days Post Tumor Challenge Percent Survival A20-KLH (BV) Mal HBSS Figure 5A: The (BV) maleimide conjugates resulted in the highest level of tumor eradicaton.

Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia. Comparison of BV vs. Hyb Derived Id Proteins Tumor Eradication is Superior with Use of Insect-Derived Idiotype Proteins Days Post Tumor Challenge Percent Survival A20-KLH (BV) A20-KLH (Hyb) HBSS Figure 5B: A20-KLH (BV) and (Hyb) Groups Were Pooled to Show Enhancement of Survival with Insect-Derived Id Proteins.

Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia. Comparison of Maleimide vs. Glutaraldehyde Conjugated Id Proteins Tumor Eradication is Superior with Use of Insect-Derived Idiotype Proteins Days Post Tumor Challenge Percent Survival A20-KLH (BV) A20-KLH (Hyb) HBSS Figure 5C: A20-KLH Maleimide and Glutaraldehyde Treated Mice Were Pooled to Show Superiority of Maleimide-Conjugated Id Proteins Compared to Glutaraldehyde Conjugates.

Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia. Comparison of CD8 vs. CD4 Depleting Antibodies CD8 + T Cells are Required for Tumor Eradication Figure 6: CD8 + T cells are required for tumor eradication. P values represent comparisons between Id-KLH treated groups and HBSS unless otherwise indicated. The results show a clear dependence on CD8 + T cells Days Post Tumor Challenge Percent Survival CD4 Depleting Ab HBSS Control Control Ab CD8 Depleting Ab P= P= P=0.9417

Insect-Derived Idiotype Enhances Cytolytic Activity Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia. Figure 7: CD8+ T cells are enhanced with insect-derived Id proteins. Primed and boosted (2 immunizations) CTLs from spleen and lymph nodes were used at an E:T ratio of 1:1, both showed significant lysis compared to control. Additionally, the BV-derived protein demonstrated statistically better lysis compared to Hyb-produced Id. P= % Lysis Control Hyb-Id BV-Id

Production of Anti-Idiotype Antibodies is not Hindered by the Presence of Mannose Residues, and is Enhanced with Maleimide Conjugation Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia. Figure 8: To evaluate the antibody responses generated by A20-KLH (BV) and (Hyb) vaccinated mice were bled and the immune sera anti-Id antibody titers were determined by ELISA (target antigen = native, hybridoma-derived Id), using an A20 anti-Id monoclonal antibody as the standard. The BV-derived Id proteins showed no reduction in anti-Id antibody titers, and the maleimide conjugated proteins showed almost double the levels of anti-Id antibodies % Lysis A20-KLH (BV) Mal HBSS A20-KLH (Hyb) Mal A20-KLH (BV) Glut A20-KLH (Hyb) Glut

Therapeutic Lymphoma Idiotype Vaccine Generated in Insect Cells Results in Mannose Receptor Targeting and Enhanced Immune Activation The insect cell-derived idiotype (Id) proteins showed a mannose-containing carbohydrate profile typical of antibodies derived from an insect cell source Only insect cell-derived Id proteins demonstrated increased binding to human dendritic cells via the mannose receptor; the binding of mammalian- derived (hybridoma) idiotype proteins was low and did not change with the addition of mannose receptor inhibitors Conclusions Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia.

Therapeutic Lymphoma Idiotype Vaccine Generated in Insect Cells Results in Mannose Receptor Targeting and Enhanced Immune Activation Insect cell-derived Id proteins induced higher surface expression of dendritic cell activation markers CD80 and CCR7 than did mamalian- derived Id Anti-mannose receptor antibodies could inhibit upregulation of DC activation markers Conclusions Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia.

Therapeutic Lymphoma Idiotype Vaccine Generated in Insect Cells Results in Mannose Receptor Targeting and Enhanced Immune Activation Vaccination of mice bearing A20 B cell lymphoma with insect cell-derived Id protein resulted in a higher proportion of survivors compared to hybridoma-derived Id (61% vs. 49%), and conjugation to KLH using maleimide further enhanced the anti-tumor efficacy over the traditional glutaraldehyde method CD8+ T cells were critical for eradication of A20 lymphoma, and T cells primed with insect cell- derived Id showed enhanced tumor cytotoxicity Conclusions Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia.

Therapeutic Lymphoma Idiotype Vaccine Generated in Insect Cells Results in Mannose Receptor Targeting and Enhanced Immune Activation Insect cell-derived Id protein did not reduce the generation of anti-idiotype antibodies compared to hybridoma-derived protein Maleimide conjugated Id-KLH, either insect- or hybridoma-derived, generated approximately 2-fold higher anti-idiotype antibody titers compared to glutaraldehyde conjugates Conclusions Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia.

Therapeutic Lymphoma Idiotype Vaccine Generated in Insect Cells Results in Mannose Receptor Targeting and Enhanced Immune Activation Compared to mammalian cell-derived Id proteins, production of recombinant Id proteins via a baculovirus- insect cell system results in a structurally different antigen with improved immunogenicity, and this may lead to improved efficacy of the final Id-KLH vaccine product Data comparing sources of recombinant Id protein tumor antigens used in therapeutic cancer vaccines suggest that post-translational modifications, namely terminal mannose residues, can significantly influence the immunological properties and eventual therapeutic efficacy of the product Conclusions Betting DJ et al. Abstract #2343. Presented December 9, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia.