Ganglioside GD2 specific monoclonal antibody 3F8: a phase I study in patients with neuroblastoma and malignant melanoma.

Cheung, Nai Kong V.; Lazarus, Hillard M.; Miraldi, Floro; Abramowsky, Carlos R.; Kallick, Steven; Saarinen, Ulla M.; Spitzer, Thomas R.; Strandjord, Sarah E.; Coccia, Peter F.; Berger, Nathan A.

doi:10.1200/jco.1987.5.9.1430

Cited by 382 publications

(214 citation statements)

References 13 publications

Supporting

Mentioning

208

Contrasting

Unclassified

Order By: Relevance

“…In this regard, a previous study involving genetically-modified ICs such that FcR-binding capability was eliminated showed that IC-mediated antitumor effects could be obtained without FcR-binding [11]. MAb therapy has been used effectively in clinical trials as single agents, including the anti-GD 2 Ab 3F8 and precursors to the hu14.18-IL2 IC including the 14.G2a murine mAb and ch14.18 chimeric mAb [4][5]14,34]. The IL2 component of the IC augments the effects of mAb, and has been shown to increase the number and activation state of NK cells, as well as to stimulate tumor cell killing by antigen-specific T-cells [37].…”

Section: Discussionmentioning

confidence: 99%

Intratumoral immunocytokine treatment results in enhanced antitumor effects

Johnson

Lum

Rakhmilevich

et al. 2008

Cancer Immunol Immunother

View full text Add to dashboard Cite

Immunocytokines (IC), consisting of tumor-specific monoclonal antibodies fused to the immunostimulatory cytokine interleukin 2 (IL2), exert significant antitumor effects in several murine tumor models. We investigated whether intratumoral (IT) administration of IC provided enhanced antitumor effects against subcutaneous tumors. Three unique ICs (huKS-IL2, hu14.18-IL2, and GcT84.66-IL2) were administered systemically or IT to evaluate their antitumor effects against tumors expressing the appropriate IC-targeted tumor antigens. The effect of IT injection of the primary tumor on a distant tumor was also evaluated. Here, we show that IT injection of IC resulted in enhanced antitumor effects against B16-KSA melanoma, NXS2 neuroblastoma, and human M21 melanoma xenografts when compared to intravenous (IV) IC injection. Resolution of both primary and distant subcutaneous tumors, and a tumor-specific memory response were demonstrated following IT treatment in immunocompetent mice bearing NXS2 tumors. The IT effect of huKS-IL2 IC was antigen-specific, enhanced compared to IL2 alone, and dose-dependent. Hu14.18-IL2 also showed greater IT effects than IL2 alone. The antitumor effect of IT IC did not always require T cells since IT IC induced antitumor effects against tumors in both SCID and nude mice. Localization studies using radiolabeled 111 In-GcT84.66-IL2 IC confirmed that IT injection resulted in a higher concentration of IC at the tumor site than IV administration. In conclusion, we suggest that IT IC is more effective than IV administration against palpable tumors. Further testing is required to determine how to potentially incorporate IT administration of IC into an antitumor regimen that optimizes local and systemic anticancer therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Intratumoral immunocytokine treatment results in enhanced antitumor effects

Johnson

Lum

Rakhmilevich

et al. 2008

Cancer Immunol Immunother

View full text Add to dashboard Cite

show abstract

“…Anti-GD2 Abs are known to induce significantly painful side effects (25)(26)(27), with occasional reports of cranial or peripheral neuropathy. Anti-GD1a Abs preferentially immunostained motor fibers thought to cause motor neuropathies such as acute motor axonal neuropathy (28).…”

Section: Discussionmentioning

confidence: 99%

Reducing Epitope Spread during Affinity Maturation of an Anti-Ganglioside GD2 Antibody

Huang²,

Ling³

et al. 2009

The Journal of Immunology

View full text Add to dashboard Cite

Ab affinity maturation in vivo is always accompanied by negative selection to maintain Ag specificity. In contrast, in vitro affinity maturation can lead to epitope spread, resulting in loss of specificity. Anti-ganglioside-GD2 mAbs are clinically effective against neuroblastoma; pain and neuropathy are major side effects. We used structural relatives of GD2 to define epitope spread during in vitro affinity maturation of an anti-GD2 single-chain variable fragment (scFv) called 5F11-scFv. Clonal dominance identified by polyclonal sequencing was confirmed by analyzing individual clones. Affinity-matured mutations were introduced into scFv-streptavidin for functional studies. Without a negative selector, 19-fold affinity improvement (clone Q, where Q is the symbol for glutamine) was associated with strong cross-reactivity with GM2 and GD1b and moderate cross-reactivity with GD3, resulting in positive immunohistochemical staining of all 13 non-neural normal human tissues, in contrast to none of 13 tissues with parental clone P. With GM2 as a negative selector, clone Y (where Y is the symbol for tyrosine) was generated with only weak cross-reactivity with GD1b, adrenal and thyroid glands, and no staining of other non-neural normal tissues. Even though there was only a 3-fold affinity improvement, clone Y showed significantly higher tumor uptake over parental clone P (134%, p = 0.04), whereas clone Q was inferior (54% of clone P; p = 0.05) as confirmed by tumor-to-normal tissue ratios across 16 organs (41% of clone P; p < 0.0001). Using the less efficient negative selector GD3, a clone mixture (Q, V, and Y, where V is the symbol for valine) emerged. We conclude that epitope spread during affinity maturation can be reduced by negative selection. Furthermore, efficiency of the negative selector depends on its cross-reactive affinity with the matured scFv.

show abstract

“…In addition, the Fc-fragment of the murine antibody may not elicit ADCC or CDC as effectively as the Fc portion of a human antibody, as described above [45,46,47,48,49].…”

Section: Gd2 and Anti-gd2 Antibody Immunotherapymentioning

confidence: 99%