Phase I Multidose-Escalation Study of the Anti-CD19 Maytansinoid Immunoconjugate SAR3419 Administered by Intravenous Infusion Every 3 Weeks to Patients With Relapsed/Refractory B-Cell Lymphoma

Younes, Anas; Kim, Stella K.; Romaguera, Jorge; Copeland, Amanda; Farial, Silvanade De Castro; Kwak, Larry W.; Fayad, Luis; Hagemeister, Frederick; Fanale, Michelle A.; Neelapu, Sattva S.; Lambert, John M.; Morariu-Zamfir, Rodica; Payrard, Sandrine; Li, Gordon

doi:10.1200/jco.2011.39.4403

Cited by 155 publications

(128 citation statements)

References 19 publications

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“…1), and thus is less susceptible to cleavage via thiol-disulfide exchange (11,12). One factor influencing the outcome of such assessments is the effect of linker choice on the pharmacokinetics of the conjugates in vivo (6,(13)(14)(15)(16). Another factor is the safety profile: for example, in preclinical rodent models, the trastuzumab-maytansinoid conjugate made with the uncleavable SMCC linker was found to be better tolerated than trastuzumab-SPP-DM1 (17,18), while, across several antibodies studied, Ab-SPP-DM1 and Ab-SPDB-DM4 were found to have similar tolerability (16).…”

Section: Antibody-maytansinoid Conjugatesmentioning

confidence: 99%

ADME of Antibody–Maytansinoid Conjugates

Erickson

Lambert

2012

AAPS J

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114

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Abstract. The concept of treating cancer with antibody-drug conjugates (ADCs) has gained momentum with the favorable activity and safety of trastuzumab emtansine (T-DM1), SAR3419, and lorvotuzumab mertansine (IMGN901). All three ADCs utilize maytansinoid cell-killing agents which target tubulin and suppress microtubule dynamics. Each ADC utilizes a different optimized chemical linker to attach the maytansinoid to the antibody. Characterizing the absorption, distribution, metabolism, and excretion (ADME) of these ADCs in preclinical animal models is important to understanding their efficacy and safety profiles. The ADME properties of these ADCs in rodents were inferred from studies with radiolabeled ADCs prepared with nonbinding antibodies since T-DM1, SAR3419, IMGN901 all lack crossreactivity with rodent antigens. For studies exploring tumor localization and activation in tumor-bearing mice, tritium-labeled T-DM1, SAR3419, and IMGN901 were utilized. The chemical nature of the linker was found to have a significant impact on the ADME properties of these ADCs-particularly on the plasma pharmacokinetics and observed catabolites in tumor and liver tissues. Despite these differences, T-DM1, SAR3419, and IMGN901 were all found to facilitate efficient deliveries of active maytansinoid catabolites to the tumor tissue in mouse xenograft models. In addition, all three ADCs were effectively detoxified during hepatobiliary elimination in rodents.

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Section: Antibody-maytansinoid Conjugatesmentioning

confidence: 99%

ADME of Antibody–Maytansinoid Conjugates

Erickson

Lambert

2012

AAPS J

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114

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“…SAR3419 consists of a humanized anti-CD19 antibody and a linker (SPDB) cleavable by disulfide reduction attached to the maytansinoid DM4 (a microtubule-disrupting agent) through lysine residues. Phase I trials of SAR3419 in relapsed and refractory NHL have also shown clinical activity (8). SGN-CD19A, another ADC targeting CD19 but with a stable linker and a less membrane-permeable auristatin, has started early clinical trials in NHL.…”

Section: Introductionmentioning

confidence: 99%

A Novel Anti-CD22 Anthracycline-Based Antibody–Drug Conjugate (ADC) That Overcomes Resistance to Auristatin-Based ADCs

Yu¹,

Zheng²,

Go³

et al. 2015

Clinical Cancer Research

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Purpose: We are interested in identifying mechanisms of resistance to the current generation of antibody-drug conjugates (ADC) and developing ADCs that can overcome this resistance.Experimental Design: Pinatuzumab vedotin (anti-CD22-vc-MMAE) and polatuzumab vedotin are ADCs that contain the microtubule inhibitor monomethyl auristatin E (MMAE) attached to the antibody by the proteasecleavable linker maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl (MC-vc-PAB). Early clinical trial data suggest that these ADCs have promising efficacy for the treatment of nonHodgkin lymphoma (NHL); however, some patients do not respond or become resistant to the ADCs. Anthracyclines are very effective in NHL, but ADCs containing the anthracycline doxorubicin were not clinically efficacious probably due to the low drug potency and inadequate linker technology. The anthracycline analogue PNU-159682 is thousands of times more cytotoxic than doxorubicin, so we used it to develop a new class of ADCs. We used the same MC-vc-PAB linker and antibody in pinatuzumab vedotin but replaced the MMAE with a derivative of PNU-159682 to make anti-CD22-NMS249 and tested it for in vivo efficacy in xenograft tumors resistant to MMAE-based ADCs.Results: We derived cell lines from in vivo xenograft tumors that were made resistant to anti-CD22-vc-MMAE and anti-CD79b-vc-MMAE. We identified P-gp (ABCB1/MDR1) as the major driver of resistance to the vc-MMAE-based conjugates. Anti-CD22-NMS249 was at least as effective as anti-CD22-vc-MMAE in xenograft models of the parental cell lines and maintained its efficacy in the resistant cell lines.Conclusions: These studies provide proof of concept for an anthracycline-based ADC that could be used to treat B-cell malignancies that are resistant to vc-MMAE conjugates.

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“…Given the association of DM4 with ocular toxicity (18,19), we chose to test auristatin-based antimesothelin ADCs using novel monoclonals to mesothelin. The most efficacious was an internalizing proteasesensitive valine-citrulline-linked monomethyl auristatin E (vcMMAE) conjugate.…”

Section: Introductionmentioning

confidence: 99%

An Antimesothelin-Monomethyl Auristatin E Conjugate with Potent Antitumor Activity in Ovarian, Pancreatic, and Mesothelioma Models

Scales¹,

Gupta²,

Pacheco³

et al. 2014

Molecular Cancer Therapeutics

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Mesothelin (MSLN) is an attractive target for antibody-drug conjugate therapy because it is highly expressed in various epithelial cancers, with normal expression limited to nondividing mesothelia. We generated novel antimesothelin antibodies and conjugated an internalizing one (7D9) to the microtubuledisrupting drugs monomethyl auristatin E (MMAE) and MMAF, finding the most effective to be MMAE with a lysosomal protease-cleavable valine-citrulline linker. The humanized (h7D9.v3) version, aMSLN-MMAE, specifically targeted mesothelin-expressing cells and inhibited their proliferation with an IC 50 of 0.3 nmol/L. Because the antitumor activity of an antimesothelin immunotoxin (SS1P) in transfected mesothelin models did not translate to the clinic, we carefully selected in vivo efficacy models endogenously expressing clinically relevant levels of mesothelin, after scoring mesothelin levels in ovarian, pancreatic, and mesothelioma tumors by immunohistochemistry. We found that endogenous mesothelin in cancer cells is upregulated in vivo and identified two suitable xenograft models for each of these three indications. A single dose of aMSLN-MMAE profoundly inhibited or regressed tumor growth in a dosedependent manner in all six models, including two patient-derived tumor xenografts. The robust and durable efficacy of aMSLN-MMAE in preclinical models of ovarian, mesothelioma, and pancreatic cancers justifies the ongoing phase I clinical trial. Mol Cancer Ther; 13(11); 2630-40. Ó2014 AACR.

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Phase I Multidose-Escalation Study of the Anti-CD19 Maytansinoid Immunoconjugate SAR3419 Administered by Intravenous Infusion Every 3 Weeks to Patients With Relapsed/Refractory B-Cell Lymphoma

Abstract: Using an every 3-week-schedule of SAR3419 for six cycles, the MTD is 160 mg/m(2). SAR3419 can be safely administered to patients with relapsed B-cell lymphoma and demonstrates promising clinical activity, including patients who were refractory to rituximab.

Cited by 155 publications

References 19 publications

ADME of Antibody–Maytansinoid Conjugates

ADME of Antibody–Maytansinoid Conjugates

A Novel Anti-CD22 Anthracycline-Based Antibody–Drug Conjugate (ADC) That Overcomes Resistance to Auristatin-Based ADCs

An Antimesothelin-Monomethyl Auristatin E Conjugate with Potent Antitumor Activity in Ovarian, Pancreatic, and Mesothelioma Models

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