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

Abstract

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 (anti-CD79b-vc-MMAE) are ADCs that contain the microtubule inhibitor monomethyl auristatin E (MMAE) attached to the antibody by the protease-cleavable linker maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl (MC-vc-PAB). Early clinical trial data suggest that these ADCs have promising efficacy for the treatment of non-Hodgkin 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.

• Authors: Shang-Fan Yu, Bing Zheng, MaryAnn Go, Jeff Lau, Susan Spencer, Helga Raab, Robert Soriano, Suchit Jhunjhunwala, Robert Cohen, Michele Caruso, Paul Polakis, John Flygare, Andrew G Polson
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 14 Pg. 3298-306 (Jul 15 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25840969 (Publication Type: Journal Article)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• 3'-deamino-3'',4'-anhydro-(2''-methoxy-3''-oxy-4''-morpholinyl)doxorubicin
• Aminobenzoates
• Anthracyclines
• Antineoplastic Agents
• Immunoconjugates
• Oligopeptides
• Sialic Acid Binding Ig-like Lectin 2
• auristatin
• Doxorubicin

Topics

• Aminobenzoates (pharmacology)
• Animals
• Anthracyclines (administration & dosage)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Doxorubicin (administration & dosage, analogs & derivatives)
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Immunoconjugates (pharmacology)
• Lymphoma, Non-Hodgkin (drug therapy)
• Mice
• Mice, Inbred ICR
• Mice, SCID
• Oligonucleotide Array Sequence Analysis
• Oligopeptides (pharmacology)
• Real-Time Polymerase Chain Reaction
• Sialic Acid Binding Ig-like Lectin 2 (immunology)
• Xenograft Model Antitumor Assays