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New Data on Novel ADC For Solid Cancer Presented at Joint EORTC NCI AACR Symposium

Published on 20th November

Clinical data on IMMU-132, an anti-TROP-2-SN-38 Anitbody-drug Conjugate currently being evaluated in patients with solid tumors, presented at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics being held November 18 – 21, 2014 at the Centre de Convencions Internacional Barcelona in Barcelona, Spain, demonstrated responses in patients with triple-negative breast cancer, small cell lung cancer, and non-small cell lung cancer (squamous cell cancer type).

The clinical benefit of IMMU-132, based on achieving partial responses and stable disease for at least 6 months after initiating therapy, was reported in 42%, 43%, and 31% of patients with advanced triple-negative breast, non-small cell lung, and small cell lung cancers, respectively.

In terms of serious adverse events (grades 3 and 4), neutropenia showed the highest rates of 16% (grade 3) and 6% (grade 4), with other side effects, such as anemia, fatigue, diarrhea, and febrile neutropenia, each constituting less than 10% grade 3 and 4 events. [1]

Clinical data reported on another antibody-drug conjugate, IMMU-130, an anti-CEACAM5-SN-38 ADC in clinical development for the treatment of metastatic colorectal cancer, demonstrated, in one particularly striking case in which the drug was administered to a patient with colon cancer with metastatic disease to the liver and lungs, an exceptional clinical benefits. The patient relapsed after receiving an irinotecan- containing regimen. Treatment with the trial drug IMMU-130 resulted in a partial response, which so far, has lasted about 11 months.

Commenting on this particular case, David M. Goldenberg, Chairman, Chief Scientific Officer and Chief Medical Officer of Immunomedics, a clinical-stage biopharmaceutical company developing IMMU-132 and IMMU-130, said: “All metastases in the liver disappeared, and only very small lesions in the lungs remain, constituting a reduction of all sites of disease by 87.5% while the patient remained in therapy for about a year.”

Platform technology: moderately-toxic drugs
In his presentation, Goldenberg differentiated the Immunomedics’ antibody-drug conjugate platform technology from other technologies.

“Our technology platforms differ from those of other companies. We do not use ‘supertoxic drugs’, such as calicheamicin. Instead, we specifically look for moderately-toxic drugs, such as SN-38, the active metabolite of the prodrug, irinotecan. We believe that the use of such a less-toxic drug, conjugated to the appropriate tumor-targeting antibody, permits greater delivery of the drug over repeated cycles of therapy, thereby improving the therapeutic index, or ratio of efficacy to toxicity, of the drug.”

He further described the technology in which SN-38 is conjugated to either anti-TROP-2 (IMMU-132) or anti-CEACAM5 (IMMU-130) antibodies, at a drug to antibody ratio or DAR of 7.6, which is about twice that of other antibody-drug conjugates.

“By giving a higher concentration of a moderately- toxic drug, we have been able to repeatedly dose patients at almost 3-times the conventional doses used for other ADCs, in a schedule of once weekly for 2 weeks, with a one week rest between cycles,” Goldenberg noted.

Site specific
The Company’s patented conjugation chemistry achieved the high DAR by site-specifically attaching SN-38 to the antibody’s interchain sulfhydryl groups without affecting the antibody’s binding to the tumor, and in a manner that preserves the drug’s activity while bound.

“When released at the site of the tumor or after being internalized by the antibody, the ADC is capable of delivering high doses selectively, whereas the amount of free drug released from the conjugate in the circulation is very low, avoiding the toxicities usually found when the parental prodrug, irinotecan, is given. This is demonstrated by the manageable neutropenia found to be the major side-effect, and the less frequent and milder diarrhea experienced compared to when irinotecan is administered,” Goldenberg explained

Safety and efficacy
“The two ADCs have now been administered to over 200 cancer patients, and we hope to have most analyzed for safety and efficacy by the end of this year. Our ADC technology clearly is different and novel, permitting long-term therapy without provoking antibodies to the ADCs, and showing acceptable and manageable toxicity, resulting in a high therapeutic index. In addition to the responses in triple- negative breast, small-cell and non-small cell lung cancers, we have observed evidence of activity also in patients with colorectal, esophageal, and urinary bladder cancers,” Cynthia L. Sullivan, Immunomedics’ President and CEO, commented.

She further added: “Our results with IMMU-132 in patients with triple-negative breast cancer will be updated in two presentations at the San Antonio Breast Cancer Symposium (SABCS) December 9-13, 2014 in San Antonio, Texas. These results will show continued encouraging results in this highly malignant and challenging form of breast cancer.”

Featured image: Dusk in Barcelona Spain. Casa Milà.  Because of its looks, the building is also called  ‘La Pedrera.’  Photo Courtesy: David Iliff . Used with permission. License: CC-BY-SA 3.0. Photo in article: David M. Goldenberg ScD.,MD, Chairman, Chief Scientific Officer and Chief Medical Officer Immunomedics, Inc. Photo Courtesy: Immunomedics, Inc.

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