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Background: Bone marrow transplantation, ex vivo gene therapies targeting hematological disorders, and other forms of adoptive cell therapies (ACT) require complete or partial removal of the host immune cells by a process called conditioning. This is usually accomplished with total body irradiation (TBI) or chemotherapy, but both modalities can result in significant toxicities, especially in elderly patients. As a result, more effective and safe alternatives to TBI and chemotherapy for conditioning prior to ACT are therefore needed. We have recently demonstrated that the murine CD45-targeting antibody 30F11 armed with the beta emitters 131Iodine or 177Lutetium successfully eliminated various cohorts of immune cells in murine models and ensured effective tumor control during adoptive T cell therapy (Dawicki W., et al. Oncotarget 2020). Here we report the results of a dose optimization study and radiation dosimetry results for 30F11 antibody labeled with the powerful alpha emitter 225Actinium (225Ac). Methods: Female C57BL/6 mice were treated with a broad dose range of 225Ac-30F11 antibody (100-500 nCi per mouse). Survival of mice was observed for 25 days post treatment, and white blood cells (WBC), red blood cells (RBC) and hematopoietic stem cells (HSC) were enumerated by flow cytometry. The cellularity of bone marrow in surviving mice was assessed histologically. Radiation dosimetry calculations were performed to yield the doses delivered to the various organs including those with significant numbers of immune cells. Results: The survival study demonstrated that all mice receiving 100 and 250 nCi doses of 225Ac-30F11 survived, 40% survived with 300 nCi, and 0% with the 400 and 500 nCi doses. While the 500 nCi group showed signs of radiation toxicity, the 100-400 nCi doses had no effect on RBC and preserved liver and kidney function. Flow cytometry and histology revealed that up to 30% of WBC and HSC were lost in the 100-250 nCi group, up to 70% in the 300 nCi group and almost complete acellularity of bone marrow was observed in 400 nCi group. Radiation dosimetry calculations determined the absorbed doses to immune organs such as bone marrow and spleen were comparable to those for beta emitters, while the doses to other organs were lower than for beta emitters. Conclusions: This study demonstrates that low doses of an 225Ac-armed CD45-targeting antibody can safely and efficiently reduce the numbers of host immune cells which would be sufficient for gene therapy or adoptive T cell therapy while high doses can completely eliminate host immune cells, thus providing the conditions for bone marrow transplant engraftment and expansion. Citation Format: Ravendra Garg, Qing Liang, Eileen M. Geoghegan, Kevin J. Allen, Wojciech Dawicki, Dale L. Ludwig, Ekaterina Dadachova. Dose optimization and radiation dosimetry of CD45-targeting 225Actinium-armed antibody as a conditioning agent for adoptive cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1518.

Acute myeloid leukemia (AML) is a complex hematological disease often occurring in older patients. While a number of new targeted therapies have been recently approved, patient outcomes remain poor. In the US, about 19,520 new cases AML occur annually and approximately 10,670 will die from the disease. Venetoclax is a promising new targeted therapy that is under regulatory review in the US for use in combination with a hypomethylating agent (HMA) or with low-dose cytarabine (LDAC) for the treatment of newly diagnosed patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. Recently, several studies have demonstrated that increased expression of Mcl-1 is a mediator of resistance to venetoclax in AML and other hematologic malignancies. Indeed, significant up-regulation of Mcl-1 has been reported in patients with relapsed/refractory AML and venetoclax treatment itself has been shown to increase Mcl-1 levels tumor cell lines. 225Ac-lintuzumab is a clinical stage radioimmunotherapy targeting CD33 that has shown evidence of single agent activity in relapsed/refractory AML. 225Ac-lintuzumab enables delivery of the potent alpha emitting warhead 225-actinium (T1/2 = 10 days; high linear energy transfer = 6.83 MeV; and short path length = 40-100 μm or about 3-5 cell diameters) directly to tumor cells. This elicits DNA cluster breaks and double strand breaks to kill within a short radius, thereby limiting damage to normal tissue. In this study, we demonstrate that 225Ac-lintuzumab is capable of dramatically enhancing the potency of venetoclax when used in combination in both venetoclax sensitive and resistant AML cell lines. AML lines U937 and OCI-AML3 are Mcl-1 positive AML lines which are highly resistant to venetoclax (IC50 > 1 μM). While treatment of these lines with single agent venetoclax at 500 nM was ineffective at suppressing tumor cell growth in either model, the combination of 40 nCi 225Ac-lintuzumab plus 500 nM venetoclax induced a statistically significant increase tumor cell killing in vitro. While 225Ac-lintuzumab can directly effect tumor cell killing by multiple mechanisms, we investigated the potential for 225Ac-lintuzumab-directed DNA damage to suppress Mcl-1 levels as a potential mechanism of enhancing the potency of venetoclax in these models. Cell lines were incubated with titrations of 225Ac-lintuzumab prior to analysis of Mcl-1 protein by ELISA. In both cell lines, treatment with 225Ac-lintuzumab lead to a significant depletion of Mcl-1 levels in cells. This supports a mechanistic basis of Mcl-1 suppression when 225Ac-lintuzumab is used in combination with venetoclax to increase the potency of resistant AML cells to the Bcl-2 inhibitor. Results of in vivo tumor xenograft studies will also be presented. Citation Format: Ravendra Garg, Eileen Geoghegan, Kevin J. Allen, Wojciech Dawicki, Ekaterina Dadachova, Dale L. Ludwig. 225Ac-CD33 Radioimmunotherapy potently increases the sensitivity of resistant acute myeloid leukemia lines to the Bcl-2 inhibitor venetoclax by mediating a reduction in cellular Mcl-1 levels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3808.

Daratumumab is a human cytolytic antibody specific for CD38 that is used clinically for treatment of patients with multiple myeloma (MM). Current therapeutic regimens require multiple injections over months of treatment. Increasing the potency of daratumumab to shorten the length of treatment would be beneficial. 225Ac is an alpha-particle emitting radionuclide that has potent cytotoxic activities over short distances, allowing for precise targeting of a lethal dose of radiation. Previously we have established that labeling daratumumab with 225Ac increased more than 10-fold its ability to kill MM cell lines in vitro (ASH 2017, Poster Number 4427). In this study we evaluated the ability of 225Ac-daratumumab to kill established tumors in mice. Mice deficient in T- and B-cells were injected subcutaneously with human MM tumor cells and once tumors reached an average volume of ~200 mm3, mice were treated with the 225Ac-daratumumab. To determine the localization of daratumumab within the tumor-bearing mice it was labeled with 111In, an γ-emitting radioisotope. 111In-daratumumab can be easily imaged and is used as a surrogate to estimate the localization of 225Ac-daratumumab. The distribution of the 111In-daratumumab was then followed for 10 days using a microSPECT/CT scanner. To evaluate the antitumor ability of the 225Ac-daratumumab, tumor-bearing mice were injected with 225Ac-daratumumab at a dose of of 400 nCi/0.3 μg of antibody, and 200 nCi/0.3 μg of antibody. As a control, mice were injected with either saline or an equivalent amount of unlabeled daratumumab. In addition, a group of mice was also treated with 30 times greater dose of unlabeled daratumumab (10 μg) - a dose which was previously shown to be effective against established tumors. 111In-daratumumab begun to accumulate in the tumor 24 hours after intraperitoneal injection and by 7 days was exclusively present in the tumor. The growth of the tumors in mice treated with 400 nCi/0.3 μg was significantly retarded compared to mice treated with equal concentration of unlabeled daratumumab or saline. Tumor growth was similar between mice treated with 400 nCi/0.3 μg of 225Ac-daratumumab and mice treated with 10 μg of unlabeled daratumumab. In conclusion, this study shows that labeling daratumumab with 225Ac increases its antitumor activity ~30-fold. This study suggests that approach to increase the potency of daratumumab via 225Ac labeling could greatly reduce the amount of daratumumab treatment needed in the clinic. This study also highlights the potential of targeting α-emitters to tumors as a viable therapeutic approach. Citation Format: Wojciech Dawicki, Kevin Allen, Rubin Jiao, Mackenzie Malo, Keisha Thomas, Mark S. Berger, Ekaterina Dadachova. Conjugation of daratumumab with 225actinium greatly increases its antitumor activity against multiple myeloma tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 760.

Purpose: Melanin has emerged as an attractive target for radioimmunotherapy (RIT) of melanoma, and a radiolabeled monoclonal antibody (mAb) 6D2 to melanin is currently in clinical evaluation. We investigated two approaches to improve the targeting of radiation to tumors using melanin-binding mAbs: (a) the use of an additional mAb to melanin could provide information on whether using antibodies to melanin can serve as a general approach to development of therapeutics for melanoma, and (b) as melanin targeting involves the antibody binding to extracellular melanin released from necrotic melanoma cells, we hypothesized that the administration of a chemotherapeutic agent followed by RIT would facilitate the delivery of radiation to the tumors due to the increased presence of free melanin. Experimental Design: We evaluated the therapeutic efficacy of two melanin-binding IgM mAbs labeled with 188Re (6D2 and 11B11). We compared the efficacy of RIT with 188Re-6D2 to chemotherapy with dacarbazine (DTIC) and to combined chemotherapy and RIT in human metastatic melanoma-bearing nude mice. Results: Therapeutic efficacy of 188Re-labeled 6D2 and 11B11 was comparable despite differences in their affinity and binding site numbers. Comparison of chemotherapy with DTIC and RIT revealed that RIT was more effective in slowing tumor growth in mice. Administration of DTIC followed by RIT was more effective than either modality alone. Conclusions: These results provide encouragement for the development of RIT for melanoma with melanin-binding mAbs and suggest that combining chemotherapy and RIT may be a promising approach for the treatment of metastatic melanoma.

Purpose: The applicability ofradioimmunotherapy with organism-specif ic monoclonal anti- bodies to treatment ofinf ectious disease in experimental models has been recently shown f fungal, bacterial, and viral infections. To identify the best delivery vehicle for radioimmunotherapy ofhuman pathogenic f Cryptococcus neoformans (CN), we have done comparative evaluation ofcapsular polysaccharide-specif ic antibodies with IgG1 and IgM isotypes and F(ab¶)2 and Fab fragments. Experimental Design: 18B7 IgG1 and 13F1 IgM and their isotype-matching controls were radiolabeled with 188 Re, and their binding to 24067 and H99 CN strains was evaluated by doing Scatchard and kinetics analyses. The doses delivered during in vitro radioimmunotherapy were estimated using a cellular dosimetry algorithm. The biodistribution of 188 Re-labeled 18B7 and 13F1and of 111 In-labeled 18B7 and its F(ab¶)2 and Fab fragments was done in A/JCr mice system- ically infected with 24067 CN strain. Results: 18B7 IgG1showed superior to 13F1IgM binding to 24067 CN (Ka =1 .7� 10 9 mol/L -1 and 5.4� 10 7 mol/L -1 , respectively). Substantial killing of24067 and H99 CN cells was achieved with 1 ACi 188 Re-18B7 (55 cGy dose), whereas no killing was observed for 1 ACi 188 Re-13F1 (2 cGy dose). In vivo 188 Re-18B7 localized specifically in the lungs of CN-infected mice, whereas uptake of 188 Re-13F1was nonspecific. 111 In-F(ab¶)2 fragments showed higher uptake in the lungs and lower in the liver at the 48-h time point in comparison with intact 111 In-18B7. Conclusions: Comparative evaluation ofIgG and IgM and ofF(ab ¶)2 and Fab fragments as potential delivery vehicles for radioimmunotherapy of cryptococcal infection strongly suggests that affinity for the target antigen is an important prerequisite for successful targeting of infection in vivo and that in vitro affinity measurements may predict the in vivo efficacy of candidate monoclonal antibodies. Current antimicrobial therapies are relatively inefficient in immunosuppressed patients, such as cancer patients or HIV-infected individuals. This problem combined with an increasing prevalence of diseases caused by highly resistant microorganisms creates an urgent need for new approaches to treatment of infectious diseases. Passive antibody therapy is a potentially useful therapeutic and preventive strategy against a variety of infectious diseases (1). The specificity of the

Antitumor diabody molecules are noncovalent single-chain Fv dimers that recapitulate the divalent binding properties of native IgG antibodies. Diabodies are capable of substantial accumulation in tumor xenografts expressing relevant antigens in immunodeficient mouse models. With a Mr of approximately 55,000, diabodies are rapidly cleared from the circulation, resulting in tumor-to-blood ratios that significantly exceed those achieved early after the administration of monoclonal antibodies. We have evaluated the therapeutic potential of the β-emitting isotope yttrium-90 (t1/2, 64 hours) conjugated to the C6.5K-A diabody that specifically targets the HER2/neu human tumor-associated antigen. We have found that a single intravenous dose of 150 μCi (200 μg) 90Y-CHX-A″–C6.5K-A diabody substantially inhibits the growth rates of established MDA-361/DYT2 human breast tumor xenografts in athymic nude mice. In contrast, 300 μCi (300 μg) 90Y-CHX-A″–C6.5K-A diabody resulted in only a minor delay in the growth of SK-OV-3 human ovarian cancer xenografts. The maximum tolerated dose was also dependent on the tumor xenograft model used. These studies indicate that genetically engineered antitumor diabody molecules can be used as effective vehicles for radioimmunotherapy.

Treatment options for acute myeloid leukemia (AML) are limited and have modest impact on 5-year survival rates in patients Citation Format: Michael S. Lebowitz, Ekaterina Revskaya, Kanam Malhotra, Amir Shahlaee, Steven Fuller, Maria R. Baer, Noa G. Holtzman, Ashkan Emadi, Ekaterina Dadachova, Hossein A. Ghanbari. Radioimmunotherapy for acute myeloid leukemia targeting human aspartyl (asparaginyl) β-hydroxylase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2650. doi:10.1158/1538-7445.AM2017-2650

Introduction: Pancreatic ductal adenocarcinoma (pancreatic cancer), is the 4th leading cause of cancer deaths. This “silent killer” is characterized by metastases occurring often before the primary tumor can be detected, resulting in a five-year survival rate of only 4%, underscoring the need for new alternative therapies. Listeria monocytogenes-based cancer therapy could be such an alternative. Our laboratory discovered that attenuated Listeria exhibits novel pathways that are particularly useful against metastatic cancer. We found that Listeria infects metastases and primary tumors, and kills tumor cells through high levels of reactive oxygen species (ROS), and that myeloid-derived suppressor cells (MDSC) deliver Listeria selectively to the tumor site(s) through chemo/cytokines produced by the tumor cells, and by protecting them, after infection, from immune clearance through their immune suppressive character. Based on these results we now use Listeria as a platform for the delivery of anticancer agents to the tumor microenvironment (TME). One novel application is the delivery of radioisotopes, which emit cytocidal radiation such as beta-particles coupled to Listeria, selectively into the tumor cells. This leads to the synergistic destruction of tumor cells by ionizing radiation, through beta-particles and through ROS generation by Listeria. We were the first to demonstrate that in a highly aggressive model of pancreatic cancer (Panc-02), therapeutic treatment with Listeria reduced the number of metastases by 50%, and when coupled to radioisotope 188-Rhenium (188Re) by 90%. This correlated with a selective accumulation of radioactivity in the metastases without significant side effects. Experimental procedures: Most recently, we explored a completely new method to RL generation using 32Phosphorus (32P), by incorporating 32P into the cell wall of Listeria (Listeria-32P) during culturing of Listeria. Panc-02 mice received 12 doses of Listeria-32P over a period of 28 days. Results: Treatment with Listeria-32P completely eliminated the metastatic cancer in 90% of the mice (visible by eye), while survival studies demonstrated that 43% of the mice were still alive and free of cancer (confirmed by histological examination) 3 months after the last treatment. Untreated mice die within 30-35 days. Most importantly, the incorporation of 32P delivered through Listeria into normal tissues including bone marrow (BM) was hardly detectable, in contrast to 32P alone, which strongly incorporated into the BM. In conclusion: We have developed a novel non-toxic strategy that is highly effective against pancreatic cancer in a preclinical model Panc-02, with a goal to treat patients with pancreatic cancer in the near future. Currently, we are testing Listeria-32P in KPC transgenic mice (conditionally express endogenous Kras-G12D and p53-R172H mutant alleles), which is a humanized model of spontaneous pancreatic cancer. Citation Format: Dinesh Chandra, Ziqiang Yuan, Steven K. Libutti, Ekaterina Dadachova, Claudia Gravekamp. Listeria-32P, a new approach to treat pancreatic cancer. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A184.

Introduction: Overall survival for patients with osteosarcoma has not meaningfully improved in over 30 years and there is a tremendous need for novel treatment strategies. Consistent overexpression of the insulin-like growth factor-2 receptor (IGF2R) has been previously demonstrated in osteosarcoma. Radioimmunotherapy (RIT) is a means of delivering cytotoxic radiation in a targeted manner, independent of specific pathway, using an antigen-specific antibody bound to a radioisotope. RIT has been successfully used in numerous oncologic scenarios. The purpose of this project was to perform a biodistribution experiment to determine if 188Re-labeled IGF2R-specific mAB preferentially localizes to tumor and to evaluate if it will effectively target and treat osteosarcoma cells without toxicity to normal tissue. Materials and Methods: Twenty SCID mice underwent heterotopic implantation of OS17. Tumor was allowed to grow to 5mm in diameter. Ten mice were randomized to receive 50μCi via intraperitoneal injection of 188Re-MEM-238 (IGF2R specific murine Ab) and 10 were randomized to receive 188Re-MOPC-21 (isotype control). Radioactivity was measured from harvested organs at 24 and 48 hours and percentage of injected radiolabeled Ab was calculated for each animal. A Scatchard plot analysis was used to calculate binding site number per OS17 cell. Twenty female SCID mice underwent heterotopic tumor implantation and thereafter were randomized into 4 groups; 300μCi 188Re-MEM-238, 300μCi188 Re-MOPC-21, unlabeled MEM-238, and untreated. Tumor size was measured over a 14-day period and repeated thereafter over a 24-day period. Immunohistochemistry was performed to assess IGF2R staining. Results: 188Re-MEM-238 preferentially localizes within the tumor at both 24 and 48 hours, reaching statistical significance at 48 hours (p = 0.001). Preferential uptake of 188Re-MEM-238 in the bone was not demonstrated. A moderate number of binding sites are available per OS17 cell however the binding constant is very high (Ka = 5.8 × 1010 M-1), which is directly proportional to the efficacy of RIT. There was nearly complete abrogation of the tumor growth by 188Re-MEM-238. There was minimal IGF2R staining in tumor treated with 188Re-MEM-238, moderate staining for tumor treated with 188Re-MOPC-21 and robust staining in the control groups. Conclusions: These findings indicate that the IGF2R expression differential between tumor and healthy tissue is substantial enough to permit for RIT targeting. Further characterization and development of this novel approach appears to be warranted. Future goals will include dosimetry calculation to establish the maximally tolerated dose, to characterize single and repeated dosing schemas across a panel of osteosarcoma tumors in both immunodeficient and immunocompetent murine models and to assess the safety of such treatments. Citation Format: David S. Geller, Ekaterina Revskaya, Mani Khan, Jonathan Morris, Richard Gorlick, Ekaterina Dadachova. Targeted therapy of osteosarcoma with radiolabeled monoclonal antibody to an insulin-like growth factor-2 receptor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1798. doi:10.1158/1538-7445.AM2015-1798

Introduction: Radioimmunotherapy (RIT) is a potent therapeutic technique that may be applicable to the treatment of numerous human cancers. Currently available RIT therapies employ beta- and alpha-emitting radionuclides. Alpha-emitters, such as 225Actinium (225Ac), have promising advantages over beta-emitters RIT such high linear energy transfer and independence of the tumor oxygenation status. RIT using 225Ac radionuclide directed by the monoclonal antibodies trastuzumab or panitumumab may provide effective, targeted antineoplastic effects. Methods: Antibodies trastuzumab to HER2/neu and panitumumab to EGFR were conjugated to the bifunctional ligands NETA, DOTA, DECA, DEPA and DETA. The conjugates were labeled with 225Ac at room temperature and 37°C. At selected time points, the mixture was analyzed by instant thin layer chromatography (ITLC). Radiolabeling reaction kinetics and yields were calculated for 225Ac and for its daughter isotopes 221Francium (221Fr) and 213Bismuth (213Bi) using the energy discrimination function of the multichannel analyzer in the gamma counter. Summary of the new data: Radiolabeling with Actinium was effective for several ligand-antibody combinations and completed within 30 min. Radiolabeling yields for 225Ac and it daughters 221Fr and 213Bi were most robust for NETA and DECA conjugates to trastuzumab and panitumumab, labeled at 37°C. Conclusion: Several novel ligands were evaluated for radiolabeling of monocloncal antibodies trastuzumab or panitumumab with 225Ac radionuclide and demonstrated fast kinetics of radiolabeling. Potential for targeted therapeutic applications will be explored in future experiments. Citation Format: Ricklie A. Julian, Chi Soo Kang, Xiang Sun, Hyun A. Song, Ekaterina Revskaya, Hyun-Soon Chong, Ekaterina Dadachova. Optimizing radioimmunotherapy techniques for the alpha-emitter 225Actinium. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3349. doi:10.1158/1538-7445.AM2015-3349

Introduction: Radioimmunotherapy (RIT) targeting intracellular antigens released in rapidly growing tumors as a result of a cellular turnover is an attractive modality for treatment of aggressive solid tumors. We are developing RIT for metastatic melanoma and HPV-related cervical cancer by targeting the intracellular antigens melanin and E6 oncoprotein, respectively, with radiolabeled specific antibodies (mAbs). In prior studies we observed that administration of unlabeled mAbs to melanin and E6 alone to tumor-bearing mice caused retardation of tumor growth. Objective: To investigate the immunological mechanisms by which unlabeled mAbs to intracellular antigens melanin and E6 oncoprotein contribute to the efficacy of RIT of melanoma and cervical cancer. Methods: The CasKi human cervical tumors and A2058 human metastatic melanoma tumors were induced in female nude mice and when the tumors diameter reached 0.5-0.7 cm, the mice with cervical tumors were treated with C1P5 mAb (IgG1 isotype) to E6 or isotype-matching control mAbs, or left untreated; and mice with melanoma tumors were given 6D2 mAb (IgM isotype) to melanin or isotype matching control mAbs; or left untreated. The tumor growth was monitored for 30 days. On day 5 and 10 post-treatment 4 mice out of each group were sacrificed and their tumors analyzed for C3 complement by Western blot and immunohistochemistry (IHC). On day 10 the tumors were analyzed by flow cytometry for the infiltration by inflammatory cells. Results: There was significant retardation of melanoma and cervical tumor growth during the observation period by 6D2 mAb to melanin and C1P5 mAb to E6 compared with untreated controls (P0.05). On days 5 and 10 C3 complement deposition was observed by Western blot and IHC in specific and non-specific mAbs-treated tumors but not in the untreated controls. The expression of C3 was more prominent on day 10. On day 10 there was infiltration of mAb-treated melanoma and cervical tumors by CD45+, CD4+ and CD8+ inflammatory cells with their levels being 30-100% greater than in untreated tumors. Conclusions: Our results of the treatment of melanoma and cervical tumors with unlabeled mAbs to intracellular antigens suggest that these mAbs can initiate complement dependent toxicity (CDC) and antibody dependent cellular toxicity (ADCC). The effect of mAbs did not depend on a mAb specificity for a particular antigen. It appeared to be dependent on the affinity of the Fc portion of mAbs for C1q molecule (CDC case) or for the Fc receptors on inflammatory cells (ADCC case). Further investigation of the contribution of unlabeled mAbs to efficacy of RIT will help to design effective treatment regiments for patients with metastatic melanoma and cervical cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5344.